[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Functional

Summary: Mutation: c.236A>G; p.Tyr79Cys | Summary: The c.236A>G (p.Tyr79Cys) variant alters the molecular function of the ELOC gene, as the Tyr79 residue is critical for forming a hydrogen bond with the Pro154 residue within the pVHL alpha domain. It has been shown to mimic the effects of pVHL deficiency on hypoxic signaling and is associated with mosaicism, suggesting it alters molecular or biochemical function.

Evidence Type: Functional Mutation: c.261_272del (p.Thr88_Pro91del) | Summary: The c.261_272del (p.Thr88_Pro91del) variant is described as an in-frame deletion that alters molecular function, contributing to the understanding of ELOC variants in RCC.

Gene→Variant (gene-first): HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys NA:c.261_272del (p.Thr88_Pro91del)

Genes: HIF1A(3091) NA

Variants: c.236A>G p.Tyr79Cys c.261_272del (p.Thr88_Pro91del)

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Oncogenic

Summary: Mutation: c.236A>G; p.Tyr79Cys | Summary: The c.236A>G (p.Tyr79Cys) variant is noted as a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC) and is implicated in tumor development due to its location in the tetramerization domain of the ELOC gene, which is essential for its function in the context of VHL disease. It is also described as a somatic variant in RCCs, contributing to tumor development in VHL-independent renal tumorigenesis.

Evidence Type: Oncogenic Mutation: c.274G>A; p.Glu92Lys | Summary: The c.274G>A (p.Glu92Lys) variant is identified as a somatic variant in RCC, contributing to tumor development.

Evidence Type: Oncogenic Mutation: c.74A>T; p.Asp25Val | Summary: The c.74A>T (p.Asp25Val) variant is reported as a somatic variant in RCC, indicating its role in tumor development.

Evidence Type: Oncogenic Mutation: c.311T>A; p.Leu104Gln | Summary: The c.311T>A (p.Leu104Gln) variant is noted as a somatic variant in RCC, suggesting its involvement in tumor progression.

Gene→Variant (gene-first): HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys RET(5979):c.274G>A VAV1(7409):p.Glu92Lys KRT7(3855):c.74A>T KRT7(3855):p.Asp25Val ELOC(6921):c.311T>A ELOC(6921):p.Leu104Gln

Genes: HIF1A(3091) RET(5979) VAV1(7409) KRT7(3855) ELOC(6921)

Variants: c.236A>G p.Tyr79Cys c.274G>A p.Glu92Lys c.74A>T p.Asp25Val c.311T>A p.Leu104Gln

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Predisposing

Summary: Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease, indicating it may confer inherited risk for the disease.

Gene→Variant (gene-first): HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys

Genes: HIF1A(3091)

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The c.236A>G (p.Tyr79Cys) variant is described as a somatic variant in renal cell carcinomas (RCCs) and contributes to tumor development in VHL-independent renal tumorigenesis. Evidence Type: Oncogenic | Mutation: c.274G>A (p.Glu92Lys) | Summary: The c.274G>A (p.Glu92Lys) variant is identified as a somatic variant in RCC, contributing to tumor development. Evidence Type: Oncogenic | Mutation: c.74A>T (p.Asp25Val) | Summary: The c.74A>T (p.Asp25Val) variant is reported as a somatic variant in RCC, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: c.311T>A (p.Leu104Gln) | Summary: The c.311T>A (p.Leu104Gln) variant is noted as a somatic variant in RCC, suggesting its involvement in tumor progression. Evidence Type: Functional | Mutation: c.261_272del (p.Thr88_Pro91del) | Summary: The c.261_272del (p.Thr88_Pro91del) variant is described as an in-frame deletion that alters molecular function, contributing to the understanding of ELOC variants in RCC.

Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys

Genes: 3091 6921 5979 3855 7409

Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Summary: Not enough information in this passage.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: c.236A>G | Summary: The c.236A>G variant is associated with mosaicism, suggesting it alters molecular or biochemical function. Evidence Type: Functional | Mutation: p.Tyr79Cys | Summary: The p.Tyr79Cys variant is associated with mosaicism, indicating it alters molecular or biochemical function.

Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: 236A>G c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The de novo missense variant c.236A>G (p.Tyr79Cys) alters the molecular function of the ELOC gene, as the Tyr79 residue is critical for forming a hydrogen bond with the Pro154 residue within the pVHL alpha domain. Evidence Type: Oncogenic | Mutation: c.236A>G (p.Tyr79Cys) | Summary: The missense variant c.236A>G (p.Tyr79Cys) is implicated in tumor development due to its location in the tetramerization domain of the ELOC gene, which is essential for its function in the context of VHL disease.

Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predisposing, Oncogenic, Functional

Summary: Evidence Type: Predisposing | Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease, indicating it may confer inherited risk for the disease. Evidence Type: Oncogenic | Mutation: c.236A>G; p.Tyr79Cys | Summary: The p.Tyr79Cys substitution is noted as a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC), suggesting it contributes to tumor development or progression. Evidence Type: Functional | Mutation: c.236A>G; p.Tyr79Cys | Summary: The variant has been shown to mimic the effects of pVHL deficiency on hypoxic signaling, indicating an alteration in molecular function.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Oncogenic, Diagnostic, Predictive

Justification: Oncogenic: The de novo pathogenic variant NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) is associated with VHL-independent renal tumorigenesis and has been previously described as a somatic variant in renal cell carcinomas (RCCs) without VHL inactivation, indicating its role in cancer development. Diagnostic: The identification of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant in a proband with VHL disease suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, thereby aiding in diagnosis. Predictive: The presence of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant has implications for predicting the development of VHL disease and associated renal tumors, as it mimics the effects of pVHL deficiency on hypoxic signaling.

Gene→Variant (gene-first): HIF1A(3091):Tyr79 HIF1A(3091):Y79 HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys ELOC(6921):c.261_272del RET(5979):c.274G>A ELOC(6921):c.311T>A KRT7(3855):c.74A>T KRT7(3855):p.Asp25Val VAV1(7409):p.Glu92Lys ELOC(6921):p.Leu104Gln ELOC(6921):p.Thr88_Pro91del

Genes: HIF1A(3091) ELOC(6921) RET(5979) KRT7(3855) VAV1(7409)

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.

Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys

Genes: 3091 6921 5979 3855 7409

Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: 236A>G c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.

Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses how the variant c.236A>G (p.Tyr79Cys) is associated with von Hippel-Lindau disease (VHL) and suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, indicating its role in disease classification. Oncogenic: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease and is linked to the development of renal cell carcinoma (RCC), suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.

Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys

Genes: 3091 6921 5979 3855 7409

Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: 236A>G c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.

Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses how the variant c.236A>G (p.Tyr79Cys) is associated with von Hippel-Lindau disease (VHL) and suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, indicating its role in disease classification. Oncogenic: The variant is described as a de novo pathogenic variant identified in a proband with VHL disease and is linked to the development of renal cell carcinoma (RCC), suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys