Submissions for variant NM_000260.4(MYO7A):c.73G>A (p.Gly25Arg)

dbSNP: rs782252317

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154329	SCV000203991	pathogenic	Rare genetic deafness	2016-06-23	criteria provided, single submitter	clinical testing	The p.Gly25Arg variant in MYO7A has now been identified in the compound heterozy gous state in six individuals with clinical features of Usher syndrome type I a nd segregated with disease in two affected siblings in one family (Liu 1997, Lev y 1997, Le Quesne Stabej 2012, Gao 2014, Lenarduzzi 2015, LMM data). It has been identified in 2/55510 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been identifie d in the general population, its frequency is low enough to be consistent with t he carrier frequency. In summary, this variant meets our criteria to be classifi ed as pathogenic for autosomal recessive Usher syndrome.
Counsyl	RCV000674570	SCV000799928	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-05-14	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073538	SCV001239085	pathogenic	Retinal dystrophy	2019-05-13	criteria provided, single submitter	clinical testing
Invitae	RCV001224495	SCV001396692	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs782252317, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 25 of the MYO7A protein (p.Gly25Arg). This missense change has been observed in individual(s) with Usher syndrome (PMID: 15660226, 22135276, 25080338). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYO7A function (PMID: 18700726). 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 MYO7A protein function. ClinVar contains an entry for this variant (Variation ID: 177722).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330513	SCV004038877	pathogenic	Usher syndrome	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.73G>A (p.Gly25Arg) results in a non-conservative amino acid change located in the Motor domain (1-729) 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 8.2e-06 in 244894 control chromosomes. c.73G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Usher Syndrome (example, Ouyang_2005, Lenarduzzi_2015, Bonnet_2016, Bahena_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Watanabe_2008). The most pronounced variant effect results in completely abolishment of the actin-translocating activity and the actin activated-ATPase activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 34148116, 27460420, 25575603, 15660226, 18700726). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001831960	SCV002093099	pathogenic	Usher syndrome type 1B	2020-11-06	no assertion criteria provided	clinical testing