Submissions for variant NM_016239.4(MYO15A):c.6437G>A (p.Arg2146Gln)

gnomAD frequency: 0.00001  dbSNP: rs760980785

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215334	SCV000271242	likely pathogenic	Rare genetic deafness	2016-03-08	criteria provided, single submitter	clinical testing	The p.Arg2146Gln variant in MYO15A has been reported in 1 Asian individual with autosomal recessive nonsyndromic hearing loss, and segregated with disease in 1 affected family member. Both siblings were compound heterozygous for this varian t and a reportedly pathogenic variant (c.4320+1G>A; Woo 2013). This variant has been identified in 1/65676 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs760980785). Although this var iant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools an d conservation analyses suggest that the p.Arg2146Gln variant may impact the pro tein, though this information alone is not predictive enough to determine pathog enicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298530	SCV002598908	uncertain significance	not specified	2022-09-27	criteria provided, single submitter	clinical testing	Variant summary: MYO15A c.6437G>A (p.Arg2146Gln) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) 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 1.2e-05 in 248620 control chromosomes (gnomAD). c.6437G>A has been reported in the literature in compound heterozygous state in two siblings, who carried a likely pathogenic variant in trans, and were affected with profound, bilateral nonsyndromic hearing loss (Woo_2013), in addition the variant was also reported in heterozygous state (i.e. without specifying a variant in trans) in an individual with nonsyndromic hearing loss in the setting of a multigene panel testing (Sloan-Heggen_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment 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 VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV003133185	SCV003817801	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2022-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV004794375	SCV005414739	likely pathogenic	not provided	2024-05-20	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: 32617096, 29849560, 30579064, 31579092, 34388253, 26242193, 26445815, 27375115, 33208113, 23865914)