Submissions for variant NM_206933.4(USH2A):c.6730G>A (p.Val2244Met)

dbSNP: rs550772689

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171525	SCV001334310	uncertain significance	Usher syndrome	2024-06-28	reviewed by expert panel	curation	The c.6730G>A (p.Val2244Met) variant in USH2A is a missense variant predicted to cause a substitution of valine by methionine at amino acid 2244. The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID: 27460420) (PM3_Supporting). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID: 27460420). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1, PM3_Supporting, PP4; Version 2; 5/15/24).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152600	SCV000201891	uncertain significance	not specified	2013-12-19	criteria provided, single submitter	clinical testing	The Val2244Met variant in USH2A has been previously reported in one individual w ith hearing loss; however variants in other genes were also identified in this i ndividual and the authors of the study attributed a homozygous variant in anothe r gene for causing the hearing loss (Shearer 2013). Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of th is variant.
Counsyl	RCV000673612	SCV000798836	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000673612	SCV000896267	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-02-04	criteria provided, single submitter	clinical testing
Invitae	RCV001241475	SCV001414497	benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001274249	SCV002569073	uncertain significance	Usher syndrome type 2A	2021-10-26	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 35 of the USH2A gene that results in the amino acid substitution of Methionine for Valine at codon 2244 was detected. The observed variant c.6730G>A (p.Val2244Met) has a minor allele frequency of 0.1% and 0.006% in the 1000 genomes and gnomAD database respectively. The in silico prediction of the variant are probably damaging by PolyPhen-2 and damaging by SIFT and MutationTaster-2. The reference codon is conserved across species. The segregation analysis showed this variant to be of maternal origin. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV001171525	SCV003927120	likely pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV003338428	SCV004047503	uncertain significance	Retinitis pigmentosa 39		criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 2244 of the USH2A protein (p.Val2244Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs550772689, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (Yuya Kobayashi et al). This variant has been observed in an individual affected retinitis pigmentosa (Keren J Carss et al). This variant has been reported to the ClinVar database as Uncertain significance. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val2244Met in USH2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as uncertaiin significance.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504879	SCV000598824	uncertain significance	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001274249	SCV001458129	uncertain significance	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001241475	SCV001954128	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001241475	SCV001973058	uncertain significance	not provided		no assertion criteria provided	clinical testing