Variant: NM_016239.4(MYO15A):c.4198G>A (p.Val1400Met)

CA8423796

632271 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 429026a9-22bf-43c4-8735-e5fb87686291

HGVS expressions

NM_016239.4:c.4198G>A
NM_016239.4(MYO15A):c.4198G>A (p.Val1400Met)
NC_000017.11:g.18131523G>A
CM000679.2:g.18131523G>A
NC_000017.10:g.18034837G>A
CM000679.1:g.18034837G>A
NC_000017.9:g.17975562G>A
NG_011634.1:g.27818G>A
NG_011634.2:g.27818G>A
ENST00000647165.2:c.4198G>A
ENST00000205890.9:c.4198G>A
ENST00000615845.4:c.4198G>A
NM_016239.3:c.4198G>A

Pathogenic

• Met criteria codes: PP1_Strong PM3_Strong PP3

• Not Met criteria codes: PM2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the c.4198G>A (p.Val1400Met) variant in the MYO15A gene is 0.01980% (7/35356) of African/African-American chromosomes by gnomAD. This variant has been reported to segregate with hearing loss in at least 3 separate families (PP1_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). This variant has been detected in 10 probands with nonsyndromic hearing loss. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, in 1 a rare variant of unknown significance was observed in trans, and in 7 the variant was observed in the homozygous state (PM3_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). Additionally, the REVEL computational prediction analysis tool produced a score of 0.891, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PP3.

Met criteria codes

• PP1_Strong: Identified in 3 separate families, each with one affected segregation, and at least one parent tested to rule out homozygous carrier status (PMIDs: 27870113, 20642360; LMM internal data).
• PM3_Strong: Identified in 7 HL probands in homozygous state and 3 HL probands in compound heterozygous state across two publications and two internal LMM cases (PMIDs: 27870113, 20642360; LMM internal data). Total of 2.25 PM3 points, rounded to 2 PM3 points, leading to PM3_Strong applied.
• PP3: REVEL = 0.891, which meets the threshold to apply PP3 (>0.7). Well conserved in UCSC.

Not Met criteria codes

• PM2: Present in 7/35356 (0.01980%) of Latino/Admixed American alleles in gnomAD.

Approved on: 2021-07-27

Published on: 2022-05-13