Submissions for variant NM_206933.4(USH2A):c.13339A>G (p.Met4447Val)

dbSNP: rs139474806

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669731	SCV000794510	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-09-27	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074211	SCV001239784	uncertain significance	Retinal dystrophy	2019-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV001244688	SCV001417926	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4447 of the USH2A protein (p.Met4447Val). This variant is present in population databases (rs139474806, gnomAD 0.08%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 29625443, 31872526, 31960602; Invitae). 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: 554155). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376262	SCV001573341	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.13339A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV001244688	SCV001774020	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35456422, 31054281, 24938718, 20507924, 23661368, 31960602, 31456290, 34721897, 33124170, 31872526, 33090715, 33946315, 32675063, 32188678, 29625443)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001003255	SCV001950421	uncertain significance	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Met4447Val variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
3billion	RCV003313971	SCV004013500	uncertain significance	Usher syndrome type 2A		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with USH2A related disorder (3billion dataset). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Met4447Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000930727). Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV001376262	SCV004208156	likely pathogenic	Retinitis pigmentosa 39	2024-03-30	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001074211	SCV004707245	likely pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003255	SCV001161336	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research