ClinVar Miner

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

dbSNP: rs139474806
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Total submissions: 10
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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 2023-10-18 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

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