Submissions for variant NM_000260.4(MYO7A):c.1184G>A (p.Arg395His)

dbSNP: rs387906700

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852003	SCV002248573	pathogenic	not provided	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 395 of the MYO7A protein (p.Arg395His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 20132242, 27013738). 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. ClinVar contains an entry for this variant (Variation ID: 29926). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg395 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23770805, 27573290). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001852003	SCV002558115	likely pathogenic	not provided	2022-07-22	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: 27013738, 20132242)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317043	SCV004020528	pathogenic	Usher syndrome	2023-06-22	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.1184G>A (p.Arg395His) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense variant (p.Arg395Cys) is classified as likely pathogenic (ClinVar). 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 5.8e-06 in 172972 control chromosomes (gnomAD). c.1184G>A has been reported in the literature in multiple individuals affected with autosomal recessive nonsyndromic hearing loss with evidence of cosegregation with disease (Hildebrand_2010, Sloan-Heggen_2015, Tang_2016), and one individual was reported as compound heterozygous with a pathogenic variant in trans. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20132242, 26445815, 27013738). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000022817	SCV000044106	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2010-06-01	no assertion criteria provided	literature only