Submissions for variant NM_206933.4(USH2A):c.4124C>T (p.Ser1375Leu)

gnomAD frequency: 0.00001  dbSNP: rs751479180

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001365783	SCV001562065	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1375 of the USH2A protein (p.Ser1375Leu). This variant is present in population databases (rs751479180, gnomAD 0.0009%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25425308, 32188678, 34781295; 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: 1056888). 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.
GeneDx	RCV001365783	SCV001789625	likely pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	Observed with a second variant (phase unknown) in unrelated patients with retinitis pigmentosa in the published literature (Colombo et al., 2018; Gao et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25425308, 29940899, 31054281, 34781295, 32188678)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155401	SCV003844962	likely pathogenic	Usher syndrome	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4124C>T (p.Ser1375Leu) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250610 control chromosomes (gnomAD). c.4124C>T has been reported in the literature in the heterozygous state in an individual affected with Usher Syndrome and in the compound heterozygous state in at least three individuals affected with retinitis pigmentosa, including two siblings where the variant was confirmed to be in trans with a pathogenic variant (e.g. Zein_2015, Colombo_2018, Gao_2019, Gao_2021, Colombo_2022). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001376389	SCV004208333	likely pathogenic	Retinitis pigmentosa 39	2024-02-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005005887	SCV005638326	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-22	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376389	SCV001573510	uncertain significance	Retinitis pigmentosa 39	2021-04-08	flagged submission	research	The USH2A c.4124C>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.