[Paper-level Aggregated] PMCID: PMC5029699

Evidence Type(s): Functional

Summary: Mutation: K650 | Summary: The K650 mutation alters molecular or biochemical function, with assessments indicating its impact on FGFR3 activity.

Evidence Type: Functional Mutation: K650E | Summary: The K650E mutation significantly increases auto-phosphorylation of FGFR3 KD, alters the conformation of the A-loop, and is associated with altered kinase activity, indicating a change in molecular function.

Evidence Type: Functional Mutation: K650N | Summary: The K650N mutation results in less activation of FGFR3 KD auto-phosphorylation compared to K650E, suggesting it alters molecular function.

Evidence Type: Functional Mutation: N540 | Summary: The N540 mutation is part of the molecular brake in the FGFR3 structure, suggesting it alters molecular or biochemical function.

Evidence Type: Functional Mutation: N540K | Summary: The N540K mutation leads to a substantial increase in auto-phosphorylation of FGFR3 KD and is located near the ATP binding pocket, indicating a change in molecular function.

Evidence Type: Functional Mutation: N540S | Summary: The N540S mutation is associated with reduced activation of FGFR3 KD auto-phosphorylation and is located near the ATP binding pocket, suggesting it may alter the molecular function of FGFR3.

Evidence Type: Functional Mutation: I538 | Summary: The I538 mutation is part of the molecular brake in the FGFR3 structure, indicating it may affect molecular or biochemical function.

Evidence Type: Functional Mutation: I538V | Summary: The I538V mutation had a substantial effect on drug binding, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: R669 | Summary: The R669 mutation alters molecular interactions and is associated with cancer, indicating its contribution to tumor development or progression.

Evidence Type: Functional Mutation: R669G | Summary: The R669G mutation is the most activating variant, resulting in increased auto-phosphorylation of FGFR3 KD, alters molecular interactions, and promotes an active conformation, indicating a change in molecular function.

Evidence Type: Functional Mutation: R669Q | Summary: The R669Q mutation results in increased auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: D641 | Summary: The D641 mutation is involved in forming a hydrogen bond with the drug JNJ42756493, indicating that it alters molecular interactions within the FGFR1 protein.

Evidence Type: Functional Mutation: D641G | Summary: The D641G mutation resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: D641N | Summary: The D641N mutation also resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: G637W | Summary: The G637W mutation resulted in kinase inactivation, demonstrating an alteration in molecular function.

Evidence Type: Functional Mutation: G697C | Summary: The G697C mutation alters molecular or biochemical function, although it does not affect kinase activity directly as measured in vitro.

Evidence Type: Functional Mutation: D617G | Summary: The D617G mutation completely abolished kinase activity, indicating that it alters molecular function.

Evidence Type: Functional Mutation: V555 | Summary: The V555 mutation is associated with an increase in kinase activity, indicating an alteration in molecular function.

Evidence Type: Functional Mutation: V555M | Summary: The V555M mutation is described as a gatekeeper mutation that may alter the molecular function of FGFR3, impacting its interaction with inhibitors.

Evidence Type: Functional Mutation: E466K | Summary: The E466K mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration.

Evidence Type: Functional Mutation: R675G | Summary: The R675G mutation alters the molecular interactions within the FGFR1 kinase domain, leading to a change in conformation that affects the overall structure and function of the protein.

Evidence Type: Functional Mutation: R675 | Summary: The R675 residue is involved in critical hydrogen bonding and van der Waals interactions that are essential for maintaining the inactive conformation of FGFR1, indicating its role in molecular function.

Evidence Type: Functional Mutation: H650 | Summary: The H650 residue participates in hydrogen bonding with R675, which is crucial for the structural integrity of the inactive FGFR1 kinase domain, highlighting its functional importance.

Evidence Type: Functional Mutation: Y653 | Summary: The Y653 residue is involved in van der Waals interactions with R675, contributing to the structural stability of the FGFR1 kinase domain and its functional state.

Gene→Variant (gene-first): FGFR3(2261):K650 FGFR3(2261):K650E FGFR3(2261):K650N FGFR3(2261):N540 FGFR3(2261):N540K FGFR3(2261):N540S FGFR2(2263):I538 FGFR2(2263):I538V FGFR3(2261):R669 FGFR3(2261):R669G FGFR3(2261):R669Q FGFR1(2260):D641 FGFR1(2260):D641G FGFR1(2260):D641N FGFR1(2260):G637W FGFR3(2261):G697C FGFR3(2261):D617G FGFR3(2261):V555 FGFR3(2261):V555M FGFR2(2263):E466K FGFR1(2260):R675G FGFR1(2260):R675 FGFR3(2261):H650 FGFR2(2263):Y653

Genes: FGFR3(2261) FGFR2(2263) FGFR1(2260)

Variants: K650 K650E K650N N540 N540K N540S I538 I538V R669 R669G R669Q D641 D641G D641N G637W G697C D617G V555 V555M E466K R675G R675 H650 Y653

[Paper-level Aggregated] PMCID: PMC5029699

Evidence Type(s): Oncogenic

Summary: Mutation: K650 | Summary: The K650 mutation in FGFR3 is identified as a frequently mutated hotspot associated with tumor development and progression, located in a hot spot within the A-loop of the FGFR3 kinase domain.

Evidence Type: Oncogenic Mutation: G697 | Summary: The G697 mutation is noted as a frequently mutated hotspot in FGFR3, suggesting its role in tumor development or progression.

Evidence Type: Oncogenic Mutation: N540 | Summary: The N540 mutation in FGFR3 contributes to tumor development and is noted in the context of cancer.

Evidence Type: Oncogenic Mutation: N540K | Summary: The N540K mutation is frequently observed in cancer, linked to a transformed phenotype and anchorage independent growth in cell lines, indicating its contribution to tumor progression.

Evidence Type: Oncogenic Mutation: R669 | Summary: The R669 mutation is situated near the A-loop of the FGFR3 kinase domain and is associated with cancer, indicating its potential role in tumor development or progression.

Evidence Type: Oncogenic Mutation: K650E | Summary: The K650E mutation is described as a highly activating variant linked to a transformed phenotype and anchorage independent growth in cell lines, suggesting its significant contribution to tumor development and progression.

Evidence Type: Oncogenic Mutation: R675G | Summary: The R675G variant in FGFR1 KD shows higher activity compared to wild type, indicating its potential role in tumor development or progression.

Evidence Type: Oncogenic Mutation: V555M | Summary: The V555M mutation in FGFR3 is described as a gatekeeper mutation that reduces drug binding, indicating its role in tumor development or progression.

Evidence Type: Oncogenic Mutation: R669G | Summary: The highly activating R669G mutation contributes to tumor development or progression, supporting its oncogenic potential.

Gene→Variant (gene-first): FGFR3(2261):K650 FGFR3(2261):G697 FGFR3(2261):N540 FGFR3(2261):N540K FGFR3(2261):R669 FGFR3(2261):K650E FGFR1(2260):R675G FGFR3(2261):V555M FGFR3(2261):R669G

Genes: FGFR3(2261) FGFR1(2260)

Variants: K650 G697 N540 N540K R669 K650E R675G V555M R669G

[Paper-level Aggregated] PMCID: PMC5029699

Evidence Type(s): Predictive

Summary: Mutation: V555M | Summary: The V555M mutation is associated with acquired resistance to FGFR inhibitors, significantly impacting the efficacy of AZ12908010 and AZD4547, and correlating with response to therapy, including JNJ42756493.

Evidence Type: Predictive Mutation: I538V | Summary: The I538V mutation is associated with measurements of Ki values for various FGFR3 inhibitors, indicating its potential role in influencing response to therapy.

Evidence Type: Predictive Mutation: K650E | Summary: The K650E mutation had moderate effects on the efficacy of all inhibitors, reducing the efficacy of FGFR-specific inhibitors AZD4547 and JNJ42756493, indicating a correlation with treatment response and resistance.

Evidence Type: Predictive Mutation: N540K | Summary: The N540K substitution affected the efficacy of AZD4547 and JNJ42756493 more significantly, suggesting its role in treatment sensitivity and resistance.

Evidence Type: Predictive Mutation: N540S | Summary: The N540S mutation had a pronounced effect on the efficacy of JNJ42756493, indicating its impact on treatment response.

Evidence Type: Predictive

Gene→Variant (gene-first): FGFR3(2261):V555M FGFR2(2263):I538V FGFR3(2261):K650E FGFR3(2261):N540K FGFR3(2261):N540S

Genes: FGFR3(2261) FGFR2(2263)

Variants: V555M I538V K650E N540K N540S

[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: N540K | Summary: The N540K mutation is reinforced as an important alteration that contributes to tumor development and progression, as it is associated with activating mutations in FGFR3. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is established as a significant alteration that contributes to tumor development and progression, being linked to the activation of FGFR3. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is noted for its role in altering the activation state of FGFR3, although it does not occur at high frequency and may not be linked to activation.

Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

Genes: 2261

Variants: K650E N540K R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: V555M | Summary: The variant V555M is associated with the expected efficacy of the inhibitor JNJ42756493, indicating a correlation with response to therapy. Evidence Type: Functional | Mutation: V561M | Summary: The variant V561M is discussed in the context of its interactions within the ATP-binding pocket, suggesting an alteration in molecular function related to drug binding.

Gene→Variant (gene-first): 2261:V555M 2260:V561M

Genes: 2261 2260

Variants: V555M V561M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: K650E | Summary: The K650E mutation reduces the efficacy of FGFR-specific inhibitors AZD4547 and JNJ42756493, indicating a correlation with resistance to these therapies. Evidence Type: Predictive | Mutation: N540K | Summary: The N540K mutation significantly reduces the efficacy of FGFR-specific inhibitors AZD4547 and JNJ42756493, suggesting a correlation with resistance to these therapies.

Gene→Variant (gene-first): 2261:K650E 2261:N540K

Genes: 2261

Variants: K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: K650E | Summary: The K650E mutation had moderate effects on the efficacy of all inhibitors, indicating a correlation with treatment response. Evidence Type: Predictive | Mutation: N540K | Summary: The N540K substitution affected the efficacy of AZD4547 more significantly, suggesting its role in treatment sensitivity. Evidence Type: Predictive | Mutation: N540S | Summary: The N540S mutation had a pronounced effect on the efficacy of JNJ42756493, indicating its impact on treatment response. Evidence Type: Predictive | Mutation: V555M | Summary: The V555M mutation conferred resistance to AZ12908010 and significantly impacted the efficacy of AZD4547, highlighting its role in treatment resistance. Evidence Type: Functional | Mutation: I538V | Summary: The I538V mutation had a substantial effect on drug binding, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: R669G | Summary: The highly activating R669G mutation contributes to tumor development or progression, supporting its oncogenic potential.

Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

Evidence Type(s): Predictive, Functional

Summary: Evidence Type: Predictive | Mutation: I538V | Summary: The I538V mutation is associated with measurements of Ki values for various FGFR3 inhibitors, indicating its potential role in influencing response to therapy. Evidence Type: Predictive | Mutation: K650E | Summary: The K650E mutation is mentioned in the context of measuring Ki values for FGFR3 inhibitors, suggesting its relevance in therapeutic response. Evidence Type: Predictive | Mutation: N540K | Summary: The N540K mutation is included in the study of Ki values for FGFR3 inhibitors, indicating its potential impact on treatment response. Evidence Type: Predictive | Mutation: N540S | Summary: The N540S mutation is part of the analysis of Ki values for FGFR3 inhibitors, suggesting its relevance in predicting therapeutic outcomes. Evidence Type: Functional | Mutation: V555M | Summary: The V555M mutation is described as a gatekeeper mutation that may alter the molecular function of FGFR3, impacting its interaction with inhibitors. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is noted for its potential allosteric effect, indicating a change in molecular function related to FGFR3. Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation may have an allosteric effect on FGFR3, suggesting a change in its molecular function. Evidence Type: Functional | Mutation: N540K | Summary: The N540K mutation is mentioned in the context of its location near the ATP binding pocket, indicating a potential alteration in molecular function. Evidence Type: Functional | Mutation: N540S | Summary: The N540S mutation is also located near the ATP binding pocket, suggesting it may alter the molecular function of FGFR3.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29

Evidence Type(s): Oncogenic, Predictive

Summary: Evidence Type: Oncogenic | Mutation: V555M | Summary: The V555M mutation in FGFR3 is described as a gatekeeper mutation that reduces drug binding, indicating its role in tumor development or progression. Evidence Type: Predictive | Mutation: V555M | Summary: The passage suggests that the V555M mutation may affect drug efficacy, implying a correlation with response or resistance to specific therapies.

Gene→Variant (gene-first): 2261:V555M

Genes: 2261

Variants: V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D641 | Summary: The D641 mutation is involved in forming a hydrogen bond with the drug JNJ42756493, indicating that it alters molecular interactions within the FGFR1 protein. Evidence Type: Functional | Mutation: L630 | Summary: The L630 mutation is part of a shallow pocket that interacts with the terminal isopropyl group of JNJ42756493, suggesting it plays a role in the molecular function of the FGFR1 binding site. Evidence Type: Functional | Mutation: V561 | Summary: The V561 mutation is described as the gatekeeper residue that is involved in the binding of JNJ42756493, indicating its role in the molecular function of FGFR1.

Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

Genes: 2260

Variants: D641 L630 V561

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation alters the conformation of the A-loop, impacting the allosteric communication within the FGFR2 kinase domain. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is suggested to disrupt inhibitory interactions near the A-loop, contributing to changes in the allosteric mechanism of FGFR1. Evidence Type: Functional | Mutation: R675G | Summary: The R675G mutation is implicated in altering the allosteric mechanism of FGFR1 by affecting the interactions involving the A-loop. Evidence Type: Functional | Mutation: R675 | Summary: The R675 mutation is associated with changes in the allosteric communication within the FGFR1 kinase domain, similar to the R675G variant.

Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

Genes: 2261 2260

Variants: K650E R669G R675 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation in FGFR3 alters molecular interactions and promotes an active conformation, as indicated by significant chemical shift perturbations observed in NMR studies.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R675G | Summary: The R675G mutation alters the molecular interactions within the FGFR1 kinase domain, leading to a change in conformation that affects the overall structure and function of the protein. Evidence Type: Functional | Mutation: R675 | Summary: The R675 residue is involved in critical hydrogen bonding and van der Waals interactions that are essential for maintaining the inactive conformation of FGFR1, indicating its role in molecular function. Evidence Type: Functional | Mutation: H650 | Summary: The H650 residue participates in hydrogen bonding with R675, which is crucial for the structural integrity of the inactive FGFR1 kinase domain, highlighting its functional importance. Evidence Type: Functional | Mutation: Y653 | Summary: The Y653 residue is involved in van der Waals interactions with R675, contributing to the structural stability of the FGFR1 kinase domain and its functional state.

Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation in FGFR3 is associated with cancer, indicating its contribution to tumor development or progression. Evidence Type: Functional | Mutation: R to G | Summary: The R to G replacement in FGFR1 KD alters the molecular activity of the protein, suggesting a functional change. Evidence Type: Oncogenic | Mutation: R675G | Summary: The R675G variant in FGFR1 KD shows higher activity compared to wild type, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

Genes: 2260 2261

Variants: R to G R669 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: D617G | Summary: The D617G mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Functional | Mutation: E466K | Summary: The E466K mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Functional | Mutation: G637W | Summary: The G637W mutation is predicted to reduce protein production or completely inactivate the kinase, indicating a functional alteration. Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation is located within an identified cluster of observed A-loop cancer mutations, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation in FGFR3 is associated with altered molecular function, as indicated by enhanced downstream signaling and increased FGFR3 phosphorylation in the NIH3T3 cell line.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: G697C | Summary: The G697C mutation does not affect kinase activity directly as measured in vitro, suggesting it may alter FGFR3 function in a cellular setting. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is associated with a transformed phenotype and anchorage independent growth in cell lines, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: N540K | Summary: The N540K mutation is also linked to a transformed phenotype and anchorage independent growth in cell lines, supporting its contribution to tumor progression.

Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

Genes: 2261

Variants: G697C K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation is associated with altered kinase activity, indicating that it affects the molecular function of the FGFR3 protein. Evidence Type: Oncogenic | Mutation: K650E | Summary: The K650E mutation is described as a highly activating variant, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D617G | Summary: The D617G mutation completely abolished kinase activity, indicating that it alters molecular function. Evidence Type: Functional | Mutation: G637W | Summary: The G637W mutation also resulted in kinase inactivation, demonstrating an alteration in molecular function.

Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: G697C | Summary: The G697C mutation is mentioned in the context of FGFR3 KD activity, indicating that it alters molecular or biochemical function. Evidence Type: Oncogenic | Mutation: G697C | Summary: The G697C mutation is described as one of the hotspots, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Predictive

Summary: Evidence Type: Functional | Mutation: D641G | Summary: The D641G mutation resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: D641N | Summary: The D641N mutation also resulted in an increase of auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function. Evidence Type: Predictive | Mutation: V555M | Summary: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to a specific therapy. Evidence Type: Functional | Mutation: V555 | Summary: The V555 mutation is associated with an increase in kinase activity, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

Genes: 2260 2261

Variants: D641G D641N V555 V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650E | Summary: The K650E mutation significantly increases auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: K650N | Summary: The K650N mutation results in less activation of FGFR3 KD auto-phosphorylation compared to K650E, suggesting it alters molecular function. Evidence Type: Functional | Mutation: N540K | Summary: The N540K mutation leads to a substantial increase in auto-phosphorylation of FGFR3 KD, indicating a change in molecular function. Evidence Type: Functional | Mutation: N540S | Summary: The N540S mutation is associated with reduced activation of FGFR3 KD auto-phosphorylation, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: R669G | Summary: The R669G mutation is the most activating variant in the assay, resulting in increased auto-phosphorylation of FGFR3 KD, indicating a change in molecular function. Evidence Type: Functional | Mutation: R669Q | Summary: The R669Q mutation also results in increased auto-phosphorylation of FGFR3 KD, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: I538V | Summary: The I538V mutation is the least activating among variants that increase FGFR3 KD auto-phosphorylation, suggesting it alters molecular function.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: K650 | Summary: The mutation FGFR3 K650 has been assessed for its functional impact, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: N540K | Summary: The mutation FGFR3 N540K has been assessed for its functional impact, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:K650 2261:N540K

Genes: 2261

Variants: K650 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: K650 | Summary: The K650 mutation is located in a hot spot within the A-loop of the FGFR3 kinase domain, suggesting its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: R669 | Summary: The R669 mutation is situated near the A-loop of the FGFR3 kinase domain, indicating its potential role in tumor development or progression. Evidence Type: Functional | Mutation: N540 | Summary: The N540 mutation is part of the molecular brake in the FGFR3 structure, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: I538 | Summary: The I538 mutation is also part of the molecular brake in the FGFR3 structure, indicating it may affect molecular or biochemical function.

Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2263 2261

Variants: I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Summary: Not enough information in this passage.

Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2261 2263

Variants: G697 I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: K650 | Summary: The K650 mutation in FGFR3 is associated with tumor development and progression, particularly in cancer contexts. Evidence Type: Oncogenic | Mutation: N540 | Summary: The N540 mutation in FGFR3 contributes to tumor development and is noted in the context of cancer. Evidence Type: Oncogenic | Mutation: N540K | Summary: The N540K mutation is frequently observed in cancer and is indicative of oncogenic behavior in FGFR3.

Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

Genes: 2261

Variants: K650 N540 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: K650 | Summary: The mutation K650 in FGFR3 is identified as a frequently mutated hotspot in cancer, indicating its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: G697 | Summary: The mutation G697 is noted as a frequently mutated hotspot in FGFR3, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

Genes: 2261

Variants: G697 G697C K650 N540

[Paper-level Aggregated] PMCID: PMC5029699

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The text discusses several mutations in the FGFR3 gene that are frequently observed in cancer, particularly highlighting the activating mutations K650E and N540K, which are associated with increased kinase activity and cancer development. Functional: The evidence indicates that specific mutations, such as K650E and N540K, significantly enhance FGFR3 kinase activity, as demonstrated by increased auto-phosphorylation and substrate phosphorylation assays. Predictive: The text mentions that certain mutations, including N540K and K650E, affect the efficacy of FGFR inhibitors, suggesting that these mutations can predict responses to targeted therapies in clinical settings. Prognostic: The presence of specific mutations in FGFR3, such as K650E and N540K, is associated with distinct changes in drug efficacy, which may have implications for patient outcomes and treatment strategies in cancer therapy.

Gene→Variant (gene-first): FGFR3(2261):D617 FGFR3(2261):D617G FGFR3(2261):G to W FGFR1(2260):G637 FGFR1(2260):G637W FGFR2(2263):E466K FGFR3(2261):R669 FGFR1(2260):D641 FGFR1(2260):L630 FGFR1(2260):V561 FGFR1(2260):D641G FGFR1(2260):D641N FGFR3(2261):V555 FGFR3(2261):V555M FGFR3(2261):G697 FGFR3(2261):G697C FGFR3(2261):K650 FGFR3(2261):N540 FGFR3(2261):K650E FGFR3(2261):N540K FGFR3(2261):H650 FGFR1(2260):R675 FGFR1(2260):R675G FGFR2(2263):Y653 FGFR2(2263):I538 FGFR2(2263):I538V FGFR3(2261):N540S FGFR3(2261):R669G FGFR3(2261):K650N FGFR3(2261):R669Q FGFR1(2260):R to G FGFR1(2260):V561M

Genes: FGFR3(2261) FGFR1(2260) FGFR2(2263)

Variants: D617 D617G G to W G637 G637W E466K R669 D641 L630 V561 D641G D641N V555 V555M G697 G697C K650 N540 K650E N540K H650 R675 R675G Y653 I538 I538V N540S R669G K650N R669Q R to G V561M

[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

Genes: 2261

Variants: K650E N540K R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.

Gene→Variant (gene-first): 2261:V555M 2260:V561M

Genes: 2261 2260

Variants: V555M V561M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:N540K

Genes: 2261

Variants: K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.

Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.

Gene→Variant (gene-first): 2261:V555M

Genes: 2261

Variants: V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.

Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

Genes: 2260

Variants: D641 L630 V561

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

Genes: 2261 2260

Variants: K650E R669G R675 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.

Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.

Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

Genes: 2260 2261

Variants: R to G R669 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.

Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.

Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

Genes: 2261

Variants: G697C K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.

Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Functional

Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

Genes: 2260 2261

Variants: D641G D641N V555 V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.

Gene→Variant (gene-first): 2261:K650 2261:N540K

Genes: 2261

Variants: K650 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2263 2261

Variants: I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2261 2263

Variants: G697 I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

Genes: 2261

Variants: K650 N540 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.

Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

Genes: 2261

Variants: G697 G697C K650 N540

[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

Genes: 2261

Variants: K650E N540K R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.

Gene→Variant (gene-first): 2261:V555M 2260:V561M

Genes: 2261 2260

Variants: V555M V561M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:N540K

Genes: 2261

Variants: K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.

Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538 I538V K650E N540 N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M

Genes: 2263 2261

Variants: I538V K650E N540K N540S R669G V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.

Gene→Variant (gene-first): 2261:V555M

Genes: 2261

Variants: V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.

Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561

Genes: 2260

Variants: D641 L630 V561

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G

Genes: 2261 2260

Variants: K650E R669G R675 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional

Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.

Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653

Genes: 2261 2260 2263

Variants: H650 R675 R675G Y653

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.

Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G

Genes: 2260 2261

Variants: R to G R669 R675G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional

Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.

Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669

Genes: 2261 2263 2260

Variants: D617G E466K G637W R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.

Gene→Variant (gene-first): 2261:R669G

Genes: 2261

Variants: R669G

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.

Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K

Genes: 2261

Variants: G697C K650E N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.

Gene→Variant (gene-first): 2261:K650E

Genes: 2261

Variants: K650E

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.

Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W

Genes: 2261 2260

Variants: D617 D617G G to W G637 G637W

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.

Gene→Variant (gene-first): 2261:G697C

Genes: 2261

Variants: G697C

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Functional

Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M

Genes: 2260 2261

Variants: D641G D641N V555 V555M

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.

Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q

Genes: 2263 2261

Variants: I538V K650E K650N N540K N540S R669G R669Q

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.

Gene→Variant (gene-first): 2261:K650 2261:N540K

Genes: 2261

Variants: K650 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2263 2261

Variants: I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669

Genes: 2261 2263

Variants: G697 I538 K650 N540 R669

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K

Genes: 2261

Variants: K650 N540 N540K

[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.

Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540

Genes: 2261

Variants: G697 G697C K650 N540