Submissions for variant NM_206933.4(USH2A):c.12806C>A (p.Pro4269His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002634333	SCV003524047	pathogenic	not provided	2022-10-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro4269 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 20507924), which suggests that this may be a clinically significant amino acid residue. 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) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function. This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099, 26927203). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 4269 of the USH2A protein (p.Pro4269His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239707	SCV005886885	uncertain significance	not specified	2025-01-29	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12806C>A (p.Pro4269His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR036116) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250928 control chromosomes. c.12806C>A has been reported in the literature in compound heterozygous individuals affected with Usher Syndrome (e.g. Baux_2014, Pierrache_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24944099, 26927203). ClinVar contains an entry for this variant (Variation ID: 2202940). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.