Submissions for variant NM_000180.4(GUCY2D):c.2595del (p.Lys866fs)

gnomAD frequency: 0.00003  dbSNP: rs1200134985

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV005053965	SCV005687755	pathogenic	GUCY2D-related recessive retinopathy	2025-01-31	reviewed by expert panel	curation	NM_000180.4(GUCY2D):c.2595del (p.Lys866ArgfsTer14) is a frameshift variant that introduces a premature stop codon into exon 14 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total frequency of 0.00001921, with 31 alleles / 1614008 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), abnormal visually evoked response, absence of medial opacities, and normal-appearing fundus, which together are specific for GUCY2D-related recessive retinopathy (total 5 points, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068218	SCV001233315	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys866Argfs*14) in the GUCY2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GUCY2D are known to be pathogenic (PMID: 10951519, 11328726). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 23035049, 29178642). ClinVar contains an entry for this variant (Variation ID: 861651). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003396718	SCV004104696	pathogenic	GUCY2D-related disorder	2023-04-19	criteria provided, single submitter	clinical testing	The GUCY2D c.2595delG variant is predicted to result in a frameshift and premature protein termination (p.Leu865Leufs*15). This variant has been reported in the presumed and confirmed compound heterozygous state in individuals with Leber congenital amaurosis (Patient 10, Jacobson et al. 2013. PubMed ID: 23035049; Supplementary Table 1A and 3, Family ID0535, Thompson et al. 2017. PubMed ID: 29178642) and in the presumed compound heterozygous state in an individual with retinal dystrophy (Table S5, Subject ID 15014189, Taylor et al. 2017. PubMed ID: 28341476). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7918194-TG-T) and is interpreted as pathogenic on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/861651/). Frameshift variants in GUCY2D are expected to be pathogenic. This variant is interpreted as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005021415	SCV005652779	pathogenic	Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i	2024-01-18	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001068218	SCV001749852	not provided	Cone-rod dystrophy 6; Leber congenital amaurosis 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.