Submissions for variant NM_206933.4(USH2A):c.12145G>A (p.Ala4049Thr)

gnomAD frequency: 0.00066  dbSNP: rs143696882

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213372	SCV000272886	uncertain significance	not specified	2015-02-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala4049Thr va riant in USH2A has not been previously reported in individuals with hearing loss , but has been identified in 0.2% (17/10368) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143696882 ). Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of this variant cannot be determined with certainty; however, the frequ ency data suggest that it is more likely to be benign.
Blueprint Genetics	RCV001074362	SCV001239938	uncertain significance	Retinal dystrophy	2019-07-23	criteria provided, single submitter	clinical testing
Invitae	RCV001241460	SCV001414478	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4049 of the USH2A protein (p.Ala4049Thr). This variant is present in population databases (rs143696882, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 28041643; Invitae). 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: 229616). 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.
GeneDx	RCV001241460	SCV001810791	uncertain significance	not provided	2020-08-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 28041643)
Myriad Genetics, Inc.	RCV001810438	SCV002060289	uncertain significance	Usher syndrome type 2A	2021-11-01	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.12145G>A(A4049T) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. A4049T has been observed in cases with relevant disease (PMID: 28041643). Functional assessments of this variant are not available in the literature. A4049T has been observed in population frequency databases (gnomAD: AFR 0.17%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.12145G>A(A4049T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213372	SCV002572372	uncertain significance	not specified	2022-08-26	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12145G>A (p.Ala4049Thr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251032 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00013 vs 0.011), allowing no conclusion about variant significance. c.12145G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals from cohorts undergoing evaluation for Inherited Retinal Disease (example, Carss_2017, Zampaglione_2020) and continues to be cited as likely pathogenic by others (example, Molina-Ramirez_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=5; Likely pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003401133	SCV004112640	likely pathogenic	USH2A-related condition	2023-07-20	criteria provided, single submitter	clinical testing	The USH2A c.12145G>A variant is predicted to result in the amino acid substitution p.Ala4049Thr. This variant has been reported along with a second USH2A variant in individuals with retinal disease (Table S2 in Carss et al. 2017. PubMed ID: 28041643; Table S2 in Zampaglione et al. 2020. PubMed ID: 32037395; Table S2 in Turro et al. 2020. PubMed ID: 32581362). Here, at PreventionGenetics, we have observed this variant along with a pathogenic USH2A variant in multiple individuals being tested for retinal dystrophies (internal data). This variant is reported in 0.17% of alleles in individuals of African descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215853640-C-T). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003462402	SCV004207696	likely pathogenic	Retinitis pigmentosa 39	2023-10-30	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504751	SCV000598772	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research