Variant: NM_016239.4(MYO15A):c.1137del (p.Tyr380fs)

CA8423030

500061 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 507ceb3d-5622-40fb-904a-ccf18ccf0973

HGVS expressions

NM_016239.4:c.1137del
NM_016239.4(MYO15A):c.1137del (p.Tyr380fs)
NC_000017.11:g.18119937del
CM000679.2:g.18119937del
NC_000017.10:g.18023251del
CM000679.1:g.18023251del
NC_000017.9:g.17963976del
NG_011634.1:g.16232del
NG_011634.2:g.16232del
ENST00000647165.2:c.1137del
ENST00000205890.9:c.1137del
ENST00000583079.1:n.770del
ENST00000615845.4:c.1137del
NM_016239.3:c.1137del

Likely Pathogenic

• Met criteria codes: PM3 PVS1

• Not Met criteria codes: PM2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 210/1179974 alleles (0.0001780 or 0.0178 %) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This variant has been detected in 3 individuals with nonsyndromic hearing loss. For each of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, but phase was not confirmed (p.Lys1003fsTer55, p.Glu209Ter, p.Arg3134Ter; PMIDs: 23208854, 28000701, 31980526; 1.5 pts. PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PVS1, PM3; Version 1; 3/20/2024).

Met criteria codes

• PM3: The p.Tyr380fsTer64 and another likely pathogenic or pathogenic variant were identified in 3 individuals with hearing loss, but phasing wasn't determined (PMIDs: 28000701, 31827275, 23208854; PM3). Two additional case observations were not counted due to phenotypes inconsistent with MYO15A: a case with hearing loss and RP and a case with progressive hearing loss (PMIDs: 24123792, 24875298). (Total PM3 points = 1.5)
• PVS1: The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/66 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PM2: The highest population minor allele frequency in gnomAD v4.0.0 is 0.0001780 (210/1179974 alleles) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met).

Approved on: 2024-03-20

Published on: 2024-03-29