Variant: NM_016239.4(MYO15A):c.9517+2T>C

CA398637054

666995 (ClinVar)

Gene: MYO15A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 8b38c152-570e-4a99-8b80-668d2c4bcc7b

HGVS expressions

NM_016239.4:c.9517+2T>C
NM_016239.4(MYO15A):c.9517+2T>C
NC_000017.11:g.18161449T>C
CM000679.2:g.18161449T>C
NC_000017.10:g.18064763T>C
CM000679.1:g.18064763T>C
NC_000017.9:g.18005488T>C
NG_011634.1:g.57744T>C
NG_011634.2:g.57744T>C
ENST00000642418.1:n.1781+2T>C
ENST00000643693.1:n.1319+2T>C
ENST00000644795.1:c.1309+2T>C
ENST00000646782.1:n.2251+2T>C
ENST00000647165.2:c.9517+2T>C
ENST00000651214.1:n.1948+2T>C
ENST00000205890.9:c.9517+2T>C
ENST00000418233.7:c.1309+2T>C
ENST00000433411.7:n.967+2T>C
ENST00000445289.6:n.447+2T>C
ENST00000473013.1:n.701+2T>C
ENST00000556535.5:c.379+2T>C
ENST00000557190.5:n.345+2T>C
ENST00000557655.5:c.*197+2T>C
ENST00000578575.1:n.80+2T>C
ENST00000579848.6:n.232+2T>C
ENST00000615845.4:c.9517+2T>C
NM_016239.3:c.9517+2T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.9517+2T>C variant in MYO15A is within the canonical splice site (+/- 1,2) of exon 57/66 and is predicted to cause altered splicing in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). This variant has been detected in 1 proband with hearing loss with a second variant of uncertain significance in MYO15A where phase was not determined (PMID: 26969326). The c.9517+2T>C variant was present in 0.002898% (1/34,510) of Latino/Admixed American alleles in gnomAD v2, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, the c.9517+2T>C variant in MYO15A meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Present in 0.002898% (1/34,510) of Latino/Admixed American alleles in gnomAD v2.
• PVS1: Predicted to cause loss of 5’ splice site in exon 57/66 of MYO15A.

Not Met criteria codes

• PM3: This variant has been detected in 1 proband with hearing loss with a second variant of uncertain significance in MYO15A where phase was not determined (PMID: 26969326).

Approved on: 2021-07-27

Published on: 2022-05-13