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

gnomAD frequency: 0.00001  dbSNP: rs202175091

Total submissions: 16

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-01-23	criteria provided, single submitter	clinical testing