Submissions for variant NM_000260.4(MYO7A):c.652G>A (p.Asp218Asn)

gnomAD frequency: 0.00006  dbSNP: rs201539845

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215956	SCV000271251	likely pathogenic	Rare genetic deafness	2017-08-17	criteria provided, single submitter	clinical testing	The p.Asp218Asn variant in MYO7A has been reported in 3 probands with a dominant family history of hearing loss, and segregated with disease in >10 affected rel atives from 2 families (Sun 2011, Iwasa 2016, LMM data). This variant has also b een identified in 8/34418 Latino chromosomes and in 5/126678 European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201539845); however, pathogenic variants may be present at a low frequen cy in the general population. Although loss of function variants in MYO7A primar ily cause autosomal recessive Usher syndrome, several missense variants have bee n reported to segregate with autosomal dominant hearing loss (Street 2004, Luije ndijk 2004, Bolz 2004, Liu 1997, Sun 2011, Sang 2013). While the underlying mech anism is unknown, these missense variants are primarily located within the conse rved motor domain, which is the same domain impacted by the p.Asp218Asn variant. In summary, although additional studies are required to fully establish its cli nical significance, the p.Asp218Asn variant is likely pathogenic for autosomal d ominant nonsyndromic hearing loss. ACMG/AMP criteria applied: PM1_Strong, PM2_Su pporting, PM3
Invitae	RCV000822163	SCV000962954	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 218 of the MYO7A protein (p.Asp218Asn). This variant is present in population databases (rs201539845, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant non-syndromic deafness (PMID: 21150918, 27911912). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29924). 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 not expected to disrupt MYO7A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000822163	SCV001810834	likely pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Reported as a heterozygous variant in unrelated individuals with non-syndromic hearing loss (Iwasa et al., 2016; Sakuma et al., 2016; Wu H et al., 2016); 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: 27911912, 27018795, 25788563, 26763877, 21150918, 31589614)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251923	SCV002523285	uncertain significance	See cases	2019-10-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP1, PP3
OMIM	RCV000022815	SCV000044104	pathogenic	Autosomal dominant nonsyndromic hearing loss 11	2011-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001275897	SCV001461548	likely pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000822163	SCV002037536	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000822163	SCV002038240	likely pathogenic	not provided		no assertion criteria provided	clinical testing