ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.10045C>T (p.Gln3349Ter)

gnomAD frequency: 0.00001  dbSNP: rs1345580310
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV002240823 SCV002512117 pathogenic Nonsyndromic genetic hearing loss 2021-09-28 reviewed by expert panel curation The allele frequency of the c.10045C>T (p.Gln3349Ter) variant in the MYO15A gene is 0.002% (2/112392) of European non-Finnish alleles by gnomAD v2.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a pathogenic variant (PM3_Supporting, Partners LMM internal data SCV001365783.1). The p.Gln3349Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 62/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Supporting, PVS1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001195428 SCV001365783 pathogenic Rare genetic deafness 2019-07-24 criteria provided, single submitter clinical testing The p.Gln3349X variant in MYO15A has not been previously reported in individuals with hearing loss. It has been identified in 0.001% (2/112392) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 3349, which is predicted to lead to a truncated or absent protein. Loss of function of the 3349 gene is an established disease mechanism in autosomal recessive hearing loss. In addition, this individual was found to harbor a multi-exon deletion in MYO15A that was confirmed in trans using the next-generation sequencing read data. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2, PM3.
Ambry Genetics RCV001266949 SCV001445130 pathogenic Inborn genetic diseases 2019-03-13 criteria provided, single submitter clinical testing

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