ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.10712C>T (p.Thr3571Met)

gnomAD frequency: 0.00001  dbSNP: rs202175091
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824782 SCV000065372 likely pathogenic Rare genetic deafness 2012-04-13 criteria provided, single submitter clinical testing This Thr3571Met variant has been identified in 12 individuals or families with U sher syndrome, 10 of whom were homozygous or compound heterozygous, and was abse nt from over 1000 controls (Jaijo 2010, Bonnet 2011, Aller 2006, Baux 2007, Na kanishi 2009, Greenstein 2012). This data suggests that this variant is likely t o be pathogenic, though additional segregation studies and/or functional analyse s are required to fully establish the pathogenicity of this variant.
SIB Swiss Institute of Bioinformatics RCV000041676 SCV000787455 likely pathogenic Usher syndrome type 2A 2018-04-16 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Usher syndrome type 2A, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Counsyl RCV000666226 SCV000790483 pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2017-04-04 criteria provided, single submitter clinical testing
Invitae RCV000804464 SCV000944375 pathogenic not provided 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3571 of the USH2A protein (p.Thr3571Met). This variant is present in population databases (rs202175091, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome type 2 (PMID: 17085681, 21569298, 28653555, 28894305). 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: 48355). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073629 SCV001239180 pathogenic Retinal dystrophy 2019-07-20 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001293034 SCV001573273 likely pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.10712C>T 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, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
INGEBI, INGEBI / CONICET RCV001544538 SCV001763584 pathogenic Nonsyndromic genetic hearing loss 2021-07-15 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.10712 C>T variant (p.T3571M) in USH2A gene has been identified in a singleton (1/16256 alleles) in african population obtained from gnomAD database, meeting PM2 rule. This variant has been identified in trans with at least 10 different pathogenic variants in Usher Syndrome Type 2A applying to PM3_VS and PP4 rules (PMID: 17085681, 17405132, 19737284, 19683999, 21569298, 25252889, 25575603, 27460420, 28653555, 28894305 and this report). The c.10712 C>T variant in trans with p.Thr5035Argfs*142 segregated correctly in a familial case with two Usher Syndrome affected siblings and three unafffected siblings, meeting PP1_Mod rule (PMID: 2525289). Taking all the evidence together: PM2, PM3_VS, PP4, PP1_Mod The c.10712 C>T variant in USH2A gene is classified as Pathogenic for Usher Syndrome type 2A.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000041676 SCV001976661 pathogenic Usher syndrome type 2A 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PP3, PP5
CeGaT Center for Human Genetics Tuebingen RCV000804464 SCV002062873 pathogenic not provided 2021-10-01 criteria provided, single submitter clinical testing
Mendelics RCV000041676 SCV002519946 pathogenic Usher syndrome type 2A 2022-05-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000666226 SCV002778965 likely pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2021-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323372 SCV004029982 pathogenic Usher syndrome 2023-07-28 criteria provided, single submitter clinical testing Variant summary: USH2A c.10712C>T (p.Thr3571Met) results in a non-conservative amino acid change located in the a fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251304 control chromosomes (i.e., 3 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10712C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Usher Syndrome (e.g., Jaijo_2010, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 19683999). Ten submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel RCV003324502 SCV004030330 likely pathogenic Retinitis pigmentosa 2023-07-24 criteria provided, single submitter research Clinical significance based on ACMG v2.0
Genome-Nilou Lab RCV001293034 SCV004182187 likely pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000041676 SCV004182188 likely pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV001293034 SCV004208336 pathogenic Retinitis pigmentosa 39 2023-08-11 criteria provided, single submitter clinical testing

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.