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]
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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: 2021-06-15
Published on: 2022-05-13

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

Uncertain Significance

Met criteria codes 1
BS1_Supporting
Not Met criteria codes 2
BP4 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Glu1499Asp variant in MYO15A has been identified in the heterozygous state in at least 4 individuals with hearing loss, 1 individual with intrauterine demise, and in 1 individual with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2, PMIDs: 27068579, 32304219). The filtering allele frequency (the lower threshold of the 95% CI of 59/35358) of the p.Glu1499Asp variant in the MYO15A gene is 0.13% for Latino/Admixed chromosomes by gnomAD v2.1, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting.
Met criteria codes
BS1_Supporting
The p.Glu1499Asp variant is present in 59/35358 Latino/Admixed alleles in gnomAD v2.1.1 (there are 2 homozygous observations in the European population). The lower bound of the 95% confidence interval is 0.13%.
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 5 heterozygous individuals identified with this variant (4 with hearing loss and one with intrauterine demise, LMM internal data SCV000711130.2, PMIDs: 27068579, 32304219)
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