Submissions for variant NM_016239.4(MYO15A):c.9861C>T (p.Gly3287=)

gnomAD frequency: 0.00011  dbSNP: rs372466080

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039001	SCV000062679	likely pathogenic	Rare genetic deafness	2020-10-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766887	SCV000618941	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Published functional studies suggest that this variant results in aberrant splicing and "skipping" of exon 61 (Hirsch et al., 2021); This variant is associated with the following publications: (PMID: 33398081, WangS2023[casereport], 33111345, 34733312)
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000677177	SCV000803286	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	research	The MYO15A c.9861C>T:p.G3287G variant has been detected in our study, in 2 Jewish Ashkenazi families, in compound heterozygosity with another known Ashkenazi MYO15A mutation: c.8183G>A:p.R2728H. Following immediate application of our findings in the genetics clinics in Israel, 5 additional families were detected with full segregation of this variant in compound heterozygosity with a known MYO15A deafness variant. Compound heterozygosity has not been detected in none if the 23 hearing members in these families. MYO15A c.9861C>T is predicted to lead to loss of splicing enhancer motifs by 4 of 6 HSF algorithms and to lead to gain of silencer motifs by 2 of 6 algorithms. Skipping of MYO16A exon 61 would lead to a message deletion of 161bp and a premature stop at codon 3266 of 3531.
Illumina Laboratory Services, Illumina	RCV000677177	SCV001286652	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-01-13	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.
Invitae	RCV000766887	SCV003470628	pathogenic	not provided	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change affects codon 3287 of the MYO15A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYO15A protein. This variant is present in population databases (rs372466080, gnomAD 0.4%). This variant has been observed in individual(s) with non-syndromic deafness (PMID: 33111345, 33398081, 34733312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 33111345, 33398081, 34733312). ClinVar contains an entry for this variant (Variation ID: 45777). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33398081). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000766887	SCV003917902	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MYO15A: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003398605	SCV004118997	likely pathogenic	MYO15A-related condition	2022-11-29	criteria provided, single submitter	clinical testing	The MYO15A c.9861C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Brownstein et al 2020. PubMed ID: 33111345; Hirsch et al 2021. PubMed ID: 33398081; Booth et al 2021. PubMed ID: 34733312). Functional in vitro studies have shown this variant results in exon skipping, a frameshift and premature termination (Hirsch et al 2021. PubMed ID: 33398081). This variant is reported in 0.41% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been described as a pathogenic founder variant in this population (http://gnomad.broadinstitute.org/variant/17-18069748-C-T; Brownstein et al 2020. PubMed ID: 33111345). This variant is interpreted as likely pathogenic.