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 - 1.2
Curation History
JSON LD for Version 1.2

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: 2019-12-17

Published on: 2019-12-18

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:c.623G>A

ENST00000670577.1:c.399G>A

ENST00000409619.6:c.2525G>A

ENST00000409709.7:c.2558G>A

ENST00000409893.5:c.2558G>A

ENST00000458169.2:c.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

PM2 PP1_Strong PS4_Supporting PP3

PM5

Evidence Links 1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.2558G>A (p.Arg853His) variant in MYO7A was present in 0.001549% (1/64572) of non-Finnish European chromosomes in gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2; https://gnomad.broadinstitute.org). This variant has been identified in at least 4 probands with ADNSHL (PS4_Supporting; PMID: 23804846, 26969326; LMM unpublished data, SCV000059742.6; Tokyo Medical Center unpublished data, SCV000882720.1). The p.Arg853His variant segregated with hearing loss in 10 additional family members from 1 family (PP1_Strong; Tokyo Medical Center unpublished data, SCV000882720.1). The REVEL computational prediction analysis tool produced a score of 0.741, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic hearing loss. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM2, PP3, PS4_Supporting.

PM2

Present in 0.001549% (1/64572) of non-Finnish European chromosomes in gnomAD

PP1_Strong

Internal data from Tokyo Medical Center: Family segregating this variant in 10 affected family members excluding the proband. All other variants identified in MYO7A in the proband were benign or did not segregate with HL.

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.

PubMed:23804846

PP3

REVEL score 0.741. No animals in UCSC database have an alternate codon at this site. Splicing is not predicted to be impacted in Alamut.

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

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