ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.6730G>A (p.Val2244Met) (rs550772689)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
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, Partners HealthCare 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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001241475 SCV001414497 uncertain significance not provided 2019-11-10 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 (PMID: 28166811). This variant has been observed in an individual affected with Usher syndrome (PMID: 27460420) and an individual affected with retinitis pigmentosa (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 166479). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504879 SCV000598824 uncertain significance Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.