Evidence Repository
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.6337A>T (p.Ile2113Phe)

CA254013

6950 (ClinVar)

Gene: MYO15A
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 32a40ffc-032f-4193-8775-6ab7c16565fe
Approved on: 2024-07-17
Published on: 2024-09-30

HGVS expressions

NM_016239.4:c.6337A>T
NM_016239.4(MYO15A):c.6337A>T (p.Ile2113Phe)
NC_000017.11:g.18145935A>T
CM000679.2:g.18145935A>T
NC_000017.10:g.18049249A>T
CM000679.1:g.18049249A>T
NC_000017.9:g.17989974A>T
NG_011634.1:g.42230A>T
NG_011634.2:g.42230A>T
ENST00000647165.2:c.6337A>T
ENST00000205890.9:c.6337A>T
ENST00000615845.4:c.6337A>T
NM_016239.3:c.6337A>T
More

Likely Pathogenic

Met criteria codes 3
PP3 PM2_Supporting PP1_Strong
Not Met criteria codes 1
PM3

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 c.6337A>T is a missense variant in MYO15A predicted to cause a substitution of isoleucine to phenylalanine at amino acid 2113. This variant is absent in gnomAD v4.1 (PM2_Supporting). However, it has been described as a founder variant with a carrier frequency of 25/100 in Bengkala, Bali (PMID: 9603736). This variant has been identified in the homozygous state in 1 Bengkala kindred with hearing loss and in the heterozygous state in one Chinese individual with hearing loss (PMIDs: 9603736, 27018975). The p.Ile2113Phe variant has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; PMID: 9603736). The REVEL computational prediction analysis tool produced a score of 0.91, which is above the threshold necessary to apply PP3 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PP3, PM2_Supporting. (The ClinGen Hearing Loss VCEP Specifications Version 1, 07/17/2024)
Met criteria codes
PP3
The REVEL score is 0.91, which is above the threshold for PP3 which is 0.7. MaxEntScan does not predict any defects in splicing.
PM2_Supporting
The p.Ile2113Phe variant is absent from gnomAD v4.1 with adequate coverage.
PP1_Strong
Two Indian families and the Bengkala kindred were tested for variants in MYO15A. The p.Ile2113Phe (referred to as p.Ile892Phe) was identified in the homozygous state in the Bengkala nuclear kindred. It segregated with disease in 6 affected family members. (Wang et al PMID: 9603736)
Not Met criteria codes
PM3
The p.Ile2113Phe (referred to as p.Ile892Phe) was identified in the homozygous state in the Bengkala nuclear kindred (Wang et al PMID:9603736, 0.25 PM3 points; PM3 not met). The variant was also identified in the heterozygous state in an individual from China. Phase and a second variant were not specified (Wu 2016 PMID: 27018795).
Curation History
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