Variant: NM_000260.4(MYO7A):c.3546C>A (p.Asn1182Lys)

CA381946913

438177 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 0ff89378-59ae-459b-9112-e954004ee08d

Approved on: 2019-10-22

Published on: 2019-10-22

HGVS expressions

NM_000260.4:c.3546C>A
NM_000260.4(MYO7A):c.3546C>A (p.Asn1182Lys)
NC_000011.10:g.77189386C>A
CM000673.2:g.77189386C>A
NC_000011.9:g.76900431C>A
CM000673.1:g.76900431C>A
NC_000011.8:g.76578079C>A
NG_009086.1:g.66122C>A
NG_009086.2:g.66141C>A
ENST00000409709.9:c.3546C>A
ENST00000670577.1:c.1387C>A
ENST00000409619.6:c.3513C>A
ENST00000409709.7:c.3546C>A
ENST00000458169.2:c.1089C>A
ENST00000458637.6:c.3546C>A
ENST00000467137.1:n.73C>A
ENST00000481328.7:n.1089C>A
NM_000260.3:c.3546C>A
NM_001127180.1:c.3546C>A
NM_001127180.2:c.3546C>A
NM_001369365.1:c.3513C>A

Likely Pathogenic

• Met criteria codes: PM2 PM3 PP3 PP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Asn1182Lys variant in MYO7A has been detected in 2 patients with Usher syndrome (PM3; PMID: 27460420, 28041643). One patient was homozygous for the variant, while the other was compound heterozygous with a likely pathogenic variant. The p.Asn1182Lys variant was absent from large population studies (PM2; https://gnomad.broadinstitute.org). At least one patient with a variant identified in this gene displayed sensorineural hearing loss and retinitis pigmentosa, features consistent with Usher syndrome (PP4). The REVEL computational prediction analysis tool produced a score of 0.833, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3, PP3, PP4.

Met criteria codes

• PM2: Absent from gnomAD with high coverage.
• PM3: 1.0 PM3 points total. 0.5 for proband from Bonnet et al., homozygous. 0.5 for proband from Carss et al., assumed to be in trans with the c.721C>T (Arg241Cys) variant in MYO7A, which is classified as likely pathogenic by Counsyl and NIHR Bioresource Rare Diseases, University of Cambridge
• PP3: REVEL score 0.833. Splicing not predicted to be impacted by Alamut. No animals in UCSC database have an alternate amino acid at this site.
• PP4: Identified in 1 French patient with Usher syndrome type 1 (Bonnet et al.) and 1 European male with Usher syndrome (Carss et al.)