Submissions for variant NM_206933.4(USH2A):c.10817T>C (p.Leu3606Pro)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002287043	SCV002577069	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20507924, 33535592, 27460420, 33576794)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002287043	SCV003524100	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 20507924, 27460420, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3606 of the USH2A protein (p.Leu3606Pro).
Baylor Genetics	RCV003471315	SCV004208375	pathogenic	Retinitis pigmentosa 39	2023-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700715	SCV005204428	likely pathogenic	Usher syndrome	2024-06-11	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.10817T>C (p.Leu3606Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes. c.10817T>C has been reported in the literature in compound heterozygous individuals affected with Usher Syndrome or Non-syndromic Retinitis Pigmentosa (Bonnet_2016, Colombo_2021, Falsini_2021, McGee_2010, Karali_2022, Reurink_2023). However, in some cases, the second allele was not specified. These data indicate that the variant is likely to 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: 27460420, 33576794, 33535592, 36460718, 20507924, 36785559). ClinVar contains an entry for this variant (Variation ID: 1707882). Based on the evidence outlined above, the variant was classified as likely pathogenic.