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	2020-05-26	reviewed by expert panel	curation	The filtering allele frequency of the c.6730G>A (p.Val2244Met) variant in the USH2A gene is 0.34% for South Asian chromosomes in gnomAD v2.1.1 (121/30614 with 95% CI), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). This variant has been detected in 1 Usher proband and 1 individual with isolated retinitis pigmentosa, both of whom also harbored a deleterious variant in USH2A; however, phasing was not performed for either proband (PM3, PMID: 27460420; PMID: 28041643). The variant was also identified in an individual with hearing loss who did not carry a second USH2A variant (PMID: 23804846). In summary, due to conflicting evidence of pathogenicity, this variant has been classified as uncertain clinical significance.ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PM3, PP4.
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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	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