Submissions for variant NM_000260.4(MYO7A):c.6487G>A (p.Gly2163Ser)

gnomAD frequency: 0.00002  dbSNP: rs747656448

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520963	SCV000617515	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the p.(G2163S) variant disrupts MYO7A binding to adaptor protein harmonin, which impacts mechanotransduction of cadherin linkages between stererocilia and microvilli (Yu et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27460420, 19375528, 12786748, 24105371, 23770805, 26561413, 19888295, 21117948, 28451532, 23226338, 10094549, 26226137, 30531642, 32747562, 28660889)
Invitae	RCV000520963	SCV000954261	pathogenic	not provided	2023-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2163 of the MYO7A protein (p.Gly2163Ser). This variant is present in population databases (rs747656448, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 10094549, 19375528, 19888295, 23770805, 26226137, 28451532). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402267). 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. For these reasons, this variant has been classified as Pathogenic.
King Laboratory, University of Washington	RCV000454276	SCV002059937	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2020-08-01	criteria provided, single submitter	research	MYO7A c.6487G>A, p.G2163S alters a highly conserved residue of MYO7A. The variant is homozygous in 12 Palestinian children from 6 different families with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and present in 7/280682 alleles on gnomAD, all heterozygotes.
3billion	RCV000454276	SCV002521671	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000402267). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235215	SCV003934406	pathogenic	Usher syndrome	2023-05-02	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.6487G>A (p.Gly2163Ser) results in a non-conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249272 control chromosomes. c.6487G>A has been reported in the literature in multiple individuals affected with autosomal recessive non-syndromic hearing loss with evidence of familial segregation including in numerous homozygotes (examples: Shazad_2013, AbuRayyan_2020). These data indicate that the variant is very 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: 32747562, 23770805). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Hereditary Research Laboratory, Bethlehem University	RCV000454276	SCV000538106	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2016-06-04	no assertion criteria provided	research	severe-profound
Counsyl	RCV000454276	SCV000794647	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2017-10-12	no assertion criteria provided	clinical testing