Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_016239.4(MYO15A):c.1171_1177dup (p.Tyr393fs)

CA913191112

623347 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 70883fee-2816-47d9-aacb-a467280a07bc

HGVS expressions

NM_016239.4:c.1171_1177dup

NM_016239.4(MYO15A):c.1171_1177dup (p.Tyr393fs)

NC_000017.11:g.18119971_18119977dup

CM000679.2:g.18119971_18119977dup

NC_000017.10:g.18023285_18023291dup

CM000679.1:g.18023285_18023291dup

NC_000017.9:g.17964010_17964016dup

NG_011634.1:g.16266_16272dup

NG_011634.2:g.16266_16272dup

ENST00000647165.2:c.1171_1177dup

ENST00000205890.9:c.1171_1177dup

ENST00000583079.1:n.804_810dup

ENST00000615845.4:c.1171_1177dup

NM_016239.3:c.1171_1177dup

Pathogenic

PM2_Supporting PP1_Strong PVS1 PM3

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1171_1177dup (p.Tyr393fs) variant in the MYO15A gene was absent from gnomAD with adequate coverage of the region (PM2_Supporting). This variant is a proposed founder variant in Oman and has been detected in 8 probands with hearing loss in the homozygous state (PM3; PMID: 27734841). This variant has been reported to segregate with hearing loss in at least 3 family members (PP1_Strong; PMID: 27734841). The p.Tyr393fs 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). 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, PP1_Strong, PM3, PVS1.

PM2_Supporting

Absent from gnomAD with adequate coverage.

PP1_Strong

Total of 4 segregations across 8 families with homozygous affected individuals.

PVS1

Out of frame duplication leading to frameshift in exon 2/66, which is a clinically significant exon.

PM3

This variant found in 8 total families in homozygous state with multiple affected individuals, only probands counted. Phase confirmed, consanguineous heterozygous parents.

Approved on: 2021-09-28

Published on: 2022-05-13

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