Variant: NM_016239.4(MYO15A):c.6337A>T (p.Ile2113Phe)

CA254013

6950 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 32a40ffc-032f-4193-8775-6ab7c16565fe

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

Likely Pathogenic

• Met criteria codes: PP1_Strong PM2_Supporting PP3

• Not Met criteria codes: PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Ile2113Phe variant in the MYO15A gene was absent from gnomAD v2.1.1 (PM2_Supporting). However, it has been described as a founder variant with a carrier frequency of 25/100 in Bengkala, Bali (PMID: 9603736). It 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 Hearing Loss Expert Panel (PP1_Strong, PM2_Supporting, PP3).

Met criteria codes

• 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)
• PM2_Supporting: The p.Ile2113Phe variant is absent from gnomAD v2..1.1 with adequate coverage.
• 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.

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).

Approved on: 2021-09-28

Published on: 2022-05-13