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 label mismatch: MYO15A vs undefined
  • 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.4497G>T (p.Glu1499Asp)

CA8423917

504630 (ClinVar)

Gene: MYO15A
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 20a31970-6b3f-4bf1-862a-d2dd952130a3
Approved on: 2025-03-12
Published on: 2025-04-22

HGVS expressions

NM_016239.4:c.4497G>T
NM_016239.4(MYO15A):c.4497G>T (p.Glu1499Asp)
NC_000017.11:g.18135725G>T
CM000679.2:g.18135725G>T
NC_000017.10:g.18039039G>T
CM000679.1:g.18039039G>T
NC_000017.9:g.17979764G>T
NG_011634.1:g.32020G>T
NG_011634.2:g.32020G>T
ENST00000647165.2:c.4497G>T
ENST00000205890.9:c.4497G>T
ENST00000615845.4:c.4497G>T
NM_016239.3:c.4497G>T
More

Likely Benign

Met criteria codes 2
BS1_Supporting BS2
Not Met criteria codes 2
BP4 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.4497G>T variant in MYO15A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1499. The filtering allele frequency of this variant in gnomAD v4.1 is 0.1325% in the Admixed American population, which is higher than the ClinGen Hearing Loss threshold of 0.07% for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.448, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO15A function (BP4 and PP3 not met). This variant has been identified in 1 proband with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2). The variant has also been detected in the homozygous state in three unaffected parents (BS2; GeneDx internal data SCV001982245.2). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025).
Met criteria codes
BS1_Supporting
In gnomAD v4.1.0, this variant has a filtering allele frequency of 0.1325% in the Admixed American population
BS2
The variant has been detected in the homozygous state in three unaffected parents.
Not Met criteria codes
BP4
The REVEL score falls between pathogenic and benign cutoffs. No splice impact is predicted and the residue is entirely conserved in vertebrates.
PM3
There are no scoreable cases. There are at least 7 heterozygous individuals identified with this variant (6 with hearing loss and one with intrauterine demise, LMM internal data SCV000711130.2, PreventionGenetics internal data SCV004750756.2, Fulgent Genetics internal data SCV002791779.1, GeneDx internal data SCV001982245.2, PMIDs: 27068579, 32304219, 36672845)
Curation History
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