Submissions for variant NM_016239.4(MYO15A):c.10181C>T (p.Ala3394Val)

gnomAD frequency: 0.00024  dbSNP: rs200249886

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216704	SCV000272085	uncertain significance	not specified	2014-12-15	criteria provided, single submitter	clinical testing	The p.Ala3394Val variant in MYO15A has not been previously reported in individua ls with hearing loss, but has been identified in 0.05% (35/64,726) of European c hromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP rs200249886). Although this variant has been seen in the general populatio n, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the p.Ala3394Val variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000279962	SCV000401220	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000584894	SCV000692900	uncertain significance	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000279962	SCV001526612	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-08-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375389	SCV001571822	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Supporting, PM2_Supporting, PP3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000584894	SCV002435764	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000584894	SCV005079435	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	Reported with a second variant, phase unknown, in an individual with hearing loss in published literature (PMID: 26969326); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 26969326)
PreventionGenetics, part of Exact Sciences	RCV004745286	SCV005352906	uncertain significance	MYO15A-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The MYO15A c.10181C>T variant is predicted to result in the amino acid substitution p.Ala3394Val. This variant was reported in an individual with nonsyndromic hearing loss (Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.