Variant: NM_016239.4(MYO15A):c.4642G>A (p.Ala1548Thr)

Version: 1.0
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CA8423973

228954 (ClinVar)

Gene: MYO15A (HGNC:51168)

Condition: autosomal recessive nonsyndromic hearing loss 3

Inheritance Mode: Autosomal recessive inheritance

UUID: 99de4974-7876-4054-8f80-a4970421a472

Approved on: 2025-10-08

Published on: 2025-12-19

HGVS expressions

NM_016239.4:c.4642G>A
NM_016239.4(MYO15A):c.4642G>A (p.Ala1548Thr)
NC_000017.11:g.18136462G>A
CM000679.2:g.18136462G>A
NC_000017.10:g.18039776G>A
CM000679.1:g.18039776G>A
NC_000017.9:g.17980501G>A
NG_011634.1:g.32757G>A
NG_011634.2:g.32757G>A
ENST00000647165.2:c.4642G>A
ENST00000205890.9:c.4642G>A
ENST00000615845.4:c.4642G>A
NM_016239.3:c.4642G>A

Likely Pathogenic

• Met criteria codes: PS3_Supporting PP3 PM2_Supporting PM3_Strong

• Not Met criteria codes: BA1 PS1 BS2 BS1 BP4

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 NM_016239.4(MYO15A):c.4642G>A variant is a missense variant predicted to cause a substitution of alanine to threonine at amino acid 1548. This variant has been reported in 2 probands with hearing loss. Both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and were confirmed in trans by family testing (PMIDs : 26561413, 33398081). An additional patient with congenital profound HL were compound heterozygous for this variant and another rare missense of unknown significance (PMID : 26915297) (PM3_Strong). The allele frequency of this variant is 0.005% (76/1180010) of European non-finnish chromosomes by gnomAD v.4, which is lower than the thresholds defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting, meeting this criterion (PM2_Supporting). A study repporting Inner hair cells derived from patient IPSc compound for this variant and another missense showed stereocilia length, electrophysiological and F-actin organization abnormalities. This phenotype has been rescued after CRISPR-Cas9 correction of the c.4642G>A variant, indicating that this variant impacts protein function (PMID: 26915297)(PS3_P). The REVEL computational prediction analysis tool produced a score of 0.884, which is above the threshold necessary to apply PP3 (PP3). In summary, this variant meets the 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: (PS3_P, PM2_P, PM3_S, PP3) (ClinGen Hearing Loss VCEP specifications version 1; 10/8/2025)

Met criteria codes

• PS3_Supporting: Inner hair cells derived from patient IPSc compound for this variant and another missense showed stereocilia length, electrophysiological and F-actin organization abnormalities. This phenotype has been rescued after CRISPR-Cas9 correction of the c.4642G>A variant, indicating that this variant impacts protein function (PMID: 26915297)(PS3_P).
• PP3: The REVEL computational prediction analysis tool produced a score of 0.884, which is above the threshold necessary to apply PP3 (PP3).
• PM2_Supporting: The allele frequency of this variant is 0.005% (76/1180010) of European non-finnish chromosomes by gnomAD v.4, which is lower than the thresholds defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PM3_Strong: This variant has been detected in 2 probands with hearing loss. Both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and were confirmed in trans by family testing), (optional - provide list of variants, PM3 points, PMIDs : 26561413, 33398081). Another patient with congenital profound HL were compound heterozygous for this variant and another rare missense of unknown significance (PMID : 26915297) (PM3_Strong).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: Same amino acid change reported in a signle patient with congenital severe HL PMID : 26969326 (c.4643C>T - p.Ala1548Thr), associated with another missense of unknown significance (c.5866C>T - p.(Arg1956Trp : rare, well predicted, never reported). These arguments doesn't allow to use PS1
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline