PMID: 16700630

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

Case#: Yzer_2006_Patient_441, female, age 3 months at diagnosis, Belgian maternal and Moroccan paternal origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0001483 (Eye poking), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Age was 15 months at time of last evaluation.

CaseNotHPOs: HP:0000613 (Photophobia), HP:0000563 (Keratoconus), HP:0001098 (Abnormal fundus morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D (or from each of the 20 exons of GUCY2D in the compound heterozygous individual with a novel variant).

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exons of the GUCY2D locus.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) and NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variants.

ClinVar: 9350, 98563

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1 The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1. Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_22597, female, diagnosed soon after birth, family origin not described

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0006934 (Congenital nystagmus), HP:0030532 (Visual acuity test abnormality), HP:0007843 (Attenuation of retinal blood vessels), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Diagnosis was made soon after birth, but an exact age is not described. Visual acuity was limited to light perception.

CaseNotHPOs: HP:0000543 (Optic disc pallor), HP:0007703 (Abnormality of retinal pigmentation)

CaseNotHPOFreeText: Most recent fundus examination was relatively normal at 25 years of age.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1.

CaseAddInfo: Parents were reported to be consanguineous. Segregation / phasing of two variants was not confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Perrault_2000_Family_9_Proband, male, age unknown, family origin in Algeria with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: N/A

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

PMID: 8944027

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

PMID: 22695961

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: GUCY2D protein-protein interaction with RD3

InteractingGene: HGNC:19689 (implicated in LCA12)

InteractionType: Physical (protein-protein) interaction

InteractionMethod: Interaction was established by coimmunoprecipitation followed by mass spectrometry (Table S1), confirmed by western blotting (Figure 2A).

InteractionEvidence: Mouse Rd3 was immunoprecipitated by monoclonal antibody and co-purifying proteins were identified by LC-MS/MS. The highest-scoring interacting partner was Gucy2e, the mouse ortholog of GUCY2D (Table S1). This was confirmed by western blotting (Figure 2A) and found to be dependent on the C-terminus of Gucy2e (Figure 5).

PMID: 21078983

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

PMID: 9618177

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

PMID: 27703005

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: Higher GUCY2D activity in the R838S variant

NonPatientCell: HEK293 cells (EFO:0001182)

GeneFunction: GO:0006182 (cGMP biosynthetic process)

GeneAlteration: Site-directed mutagenesis was used to introduce the substitution encoding the R838S substitution into the gene expression construct (PMID: 15504042).

FunctionalEvidence: The variant exhibits higher activity than the wild-type in HEK293 cells, with enhanced Ca2+ sensitivity (Figure 1A), higher GCAP1 affinity, (Figure 1B), and reduced sensitivity to RD3 inhibition (Figure 1C).

FAVariants: NM_000180.4(GUCY2D):c.2512C>A (p.Arg838Ser) (ClinVar: 98568)