Submissions for variant NM_206933.4(USH2A):c.12332C>T (p.Ser4111Phe)

gnomAD frequency: 0.00009  dbSNP: rs142095945

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041718	SCV000065414	uncertain significance	not specified	2011-04-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser4111Phe vari ant in USH2A has not been reported in the literature; however, this variant has been identified by our laboratory in two other individual with hearing loss; nei ther of whom had a second USH2A variant. Computational analyses (biochemical ami no acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In summary, the clinical significance of t his variant cannot be determined with certainty at this time; however, based upo n this data we would lean towards a more likely benign interpretation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241616	SCV001414646	pathogenic	not provided	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 4111 of the USH2A protein (p.Ser4111Phe). This variant is present in population databases (rs142095945, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of USH2A-related conditions ‚Äã (PMID: 30902645, 32037395; internal data). 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: 48396). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Department of Genetics, Fundacion Jimenez Diaz University Hospital	RCV001270357	SCV001450584	uncertain significance	Retinitis pigmentosa		criteria provided, single submitter	clinical testing	This variant is present in population databases (rs142095945, gnomAD_exomes 0.008%), missense variant in a gene that has a low rate of benign missense variation, predicted benign by in-silico pathogenicity predictors. (ACMG: PM2 Moderate, PP2 Supporting, BP4 Supporting). Found in trans with variant NM_206933:c.12332C>T)
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376289	SCV001573379	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.12332C>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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002496660	SCV002816042	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-08-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376289	SCV004208178	likely pathogenic	Retinitis pigmentosa 39	2024-03-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814975	SCV005070294	uncertain significance	Retinal dystrophy	2013-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001376289	SCV005087213	uncertain significance	Retinitis pigmentosa 39	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Retinitis pigmentosa 39 (MIM#613809) and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in two patients with inherited retinal dystrophy (PMID: 32037395, 33623043) and both classified as VUS. It has also been reported as VUS and pathogenic in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001274935	SCV001459517	uncertain significance	Usher syndrome type 2A	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732591	SCV005356706	likely pathogenic	USH2A-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The USH2A c.12332C>T variant is predicted to result in the amino acid substitution p.Ser4111Phe. This variant has been reported along with a second USH2A variant in individuals with retinitis pigmentosa (Table S2, Martin-Merida et al. 2019. PubMed ID: 30902645; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.