Submissions for variant NM_000180.4(GUCY2D):c.2182G>A (p.Asp728Asn)

gnomAD frequency: 0.00001  dbSNP: rs766646217

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074405	SCV001239986	likely pathogenic	Retinal dystrophy	2019-08-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862558	SCV002182629	likely pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 728 of the GUCY2D protein (p.Asp728Asn). This variant is present in population databases (rs766646217, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and/or GUCY2D-related conditions (PMID: 21602930, 34048777; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 866419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GUCY2D protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702630	SCV005204052	uncertain significance	not specified	2024-06-21	criteria provided, single submitter	clinical testing	Variant summary: GUCY2D c.2182G>A (p.Asp728Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251038 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2182G>A has been reported in the literature in compound heterozygous individuals affected with Leber Congenital Amaurosis (CoppietersZ_2012, Li_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22261762, 21602930). ClinVar contains an entry for this variant (Variation ID: 866419). Based on the evidence outlined above, the variant was classified as uncertain significance.