Submissions for variant NM_206933.4(USH2A):c.14287G>A (p.Gly4763Arg)

dbSNP: rs397517990

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041756	SCV000065452	likely pathogenic	Rare genetic deafness	2010-09-27	criteria provided, single submitter	clinical testing	The Gly4763Arg variant in USH2A has been reported in an individual with Usher sy ndrome and in an individual with nonsyndromic retinitis pigmentosa (McGee 2010). In addition, this residue is conserved in mammals. Furthermore, we have identif ied the Gly4763Arg variant in combination with a pathogenic USH2A variant in two siblings with Usher syndrome. In summary, this variant is likely to be pathogen ic.
Counsyl	RCV000665736	SCV000789903	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-10-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057445	SCV001221940	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4763 of the USH2A protein (p.Gly4763Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Usher syndrome (PMID: 25649381, 27460420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48433). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198544	SCV001369522	likely pathogenic	Usher syndrome type 2A	2019-10-28	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Genome-Nilou Lab	RCV003450788	SCV004183084	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001198544	SCV004183085	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003450788	SCV004208299	pathogenic	Retinitis pigmentosa 39	2024-03-22	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV003450788	SCV005881591	likely pathogenic	Retinitis pigmentosa 39	2025-02-05	criteria provided, single submitter	clinical testing	Another variant with the same amino acid change has been classified as pathogenic/likely pathogenic (PS1, p.Gly4763Arg). Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Variant is not found in gnomAD genomes and homozygous allele count in gnomAD exomes is less than 0 (PM2). Other variants at this amino acid residue have been classified as pathogenic/likely pathogenic (PM5, p.Gly4763Glu; p.Gly4763Val)
Dept Of Ophthalmology, Nagoya University	RCV003887895	SCV004707214	uncertain significance	Retinal dystrophy	2023-10-01	flagged submission	research