The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_016239.4(MYO15A):c.996C>G (p.Tyr332Ter)

CA8422996

505185 (ClinVar)

Gene: MYO15A
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
UUID: 5d598ebb-7674-454d-891d-d9ddfdccee01
Approved on: 2024-07-23
Published on: 2024-10-01

HGVS expressions

NM_016239.4:c.996C>G
NM_016239.4(MYO15A):c.996C>G (p.Tyr332Ter)
NC_000017.11:g.18119796C>G
CM000679.2:g.18119796C>G
NC_000017.10:g.18023110C>G
CM000679.1:g.18023110C>G
NC_000017.9:g.17963835C>G
NG_011634.1:g.16091C>G
NG_011634.2:g.16091C>G
ENST00000647165.2:c.996C>G
ENST00000205890.9:c.996C>G
ENST00000583079.1:n.629C>G
ENST00000615845.4:c.996C>G
NM_016239.3:c.996C>G
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Pathogenic

Met criteria codes 3
PVS1 PM3_Supporting PM2_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The allele frequency of the c.996C>G (p.Tyr332Ter) variant in the MYO15A gene is 0.004% (50/1179998) of European non-Finnish alleles by gnomAD v4.1.1, 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). The p.Tyr332Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting). 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, PVS1, PM3_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024)
Met criteria codes
PVS1
Premature stop codon in exon 2/66, which is a clinically significant exon.
PM3_Supporting
One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting)
PM2_Supporting
Present in 0.004% (50/1179998) of European non-Finnish alleles in gnomAD v4.1.0, which meets the threshold to apply PM2_P (<0.007%).
Curation History
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