Submissions for variant NM_206933.4(USH2A):c.4732C>T (p.Arg1578Cys)

gnomAD frequency: 0.00002  dbSNP: rs201529124

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001067861	SCV001232942	pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1578 of the USH2A protein (p.Arg1578Cys). This variant is present in population databases (rs201529124, gnomAD 0.008%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 22135276, 24618324, 29142287, 29625443). 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: 861348). 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.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376322	SCV001573426	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.4732C>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, PP3, PP1, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282450	SCV002572153	pathogenic	Usher syndrome	2022-08-18	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4732C>T (p.Arg1578Cys) results in a non-conservative amino acid change located in the laminin G domain (IPR001791) of the encoded protein sequence. Three out of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251166 control chromosomes (gnomAD). c.4732C>T has been reported in the literature in multiple biallelic individuals affected with Usher Syndrome and/or retinitis pigmentosa (e.g. Le Quesne Stabej_2012, Jinda_2014, Pierrache_2016, Eandi_2017, Sun_2018, Karali_2019, Mansard_2021, Bahena_2022). These data indicate that the variant is very likely to be 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. All classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV001376322	SCV004182205	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003455294	SCV004182208	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376322	SCV004208143	pathogenic	Retinitis pigmentosa 39	2023-10-21	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001067861	SCV001924929	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001067861	SCV001971959	pathogenic	not provided		no assertion criteria provided	clinical testing
OMIM	RCV001376322	SCV003841033	pathogenic	Retinitis pigmentosa 39	2023-04-17	no assertion criteria provided	literature only