Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000260.4(MYO7A):c.2558G>A (p.Arg853His)

Curation Version - 1.3
Curation History
JSON LD for Version 1.3

CA132255

43186 (ClinVar)

Gene: MYO7A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c33ae219-757e-4113-a157-ae454a79015c

Approved on: 2022-10-31

Published on: 2023-01-25

HGVS expressions

NM_000260.4:c.2558G>A

NM_000260.4(MYO7A):c.2558G>A (p.Arg853His)

NC_000011.10:g.77179925G>A

CM000673.2:g.77179925G>A

NC_000011.9:g.76890971G>A

CM000673.1:g.76890971G>A

NC_000011.8:g.76568619G>A

NG_009086.1:g.56662G>A

NG_009086.2:g.56680G>A

ENST00000409709.9:c.2558G>A

ENST00000409893.6:n.623G>A

ENST00000670577.1:n.399G>A

ENST00000409619.6:c.2525G>A

ENST00000409709.7:c.2558G>A

ENST00000409893.5:c.2558G>A

ENST00000458169.2:n.101G>A

ENST00000458637.6:c.2558G>A

ENST00000481328.7:n.101G>A

ENST00000620575.4:c.2558G>A

NM_000260.3:c.2558G>A

NM_001127179.2:c.2558G>A

NM_001127180.1:c.2558G>A

NM_001127180.2:c.2558G>A

NM_001369365.1:c.2525G>A

Likely Pathogenic

PP1_Strong PP3 PM2_Supporting PS4_Supporting

PM5

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022).

PP1_Strong

The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363).

PP3

The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PS4_Supporting

1 proband from Shearer 2013/Sloan-Heggen 2016 2 probands from LMM internal data (SCV000059742.6) -5mo white female with congenital moderate SNHL, het. for this variant. Also het. for 2 variants in PCDH15, either benign or benign/VUS (ClinVar ID: 46434, 46485) -Not counted: 1yo male with congenital sloping mild-moderate SNHL. Carried another variant in MYO7A (VUS, ClinVar ID: 178990), which unaffected father carried. However, mother carried R853H and was also unaffected.

PM5

2 other variants in this codon: c.2558G>T, VUS in ClinVar, and c.2557C>T (not in ClinVar, and not enough published evidence to reach LP).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.