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.3862G>C (p.Ala1288Pro)

CA6198221

866837 (ClinVar)

Gene: MYO7A (HGNC:4647)

Condition: nonsyndromic genetic deafness (MONDO:0019497)

Inheritance Mode: Autosomal recessive inheritance

UUID: 647cd6e5-0b17-415f-9309-9955f27e6ce8

Approved on: 2022-12-21

Published on: 2023-02-06

HGVS expressions

NM_000260.4:c.3862G>C

NM_000260.4(MYO7A):c.3862G>C (p.Ala1288Pro)

NC_000011.10:g.77190808G>C

CM000673.2:g.77190808G>C

NC_000011.9:g.76901853G>C

CM000673.1:g.76901853G>C

NC_000011.8:g.76579501G>C

NG_009086.1:g.67544G>C

NG_009086.2:g.67563G>C

ENST00000409709.9:c.3862G>C

ENST00000670577.1:n.1703G>C

ENST00000409619.6:c.3829G>C

ENST00000409709.7:c.3862G>C

ENST00000458169.2:n.1405G>C

ENST00000458637.6:c.3862G>C

ENST00000467137.1:n.389G>C

ENST00000481328.7:n.1405G>C

NM_000260.3:c.3862G>C

NM_001127180.1:c.3862G>C

NM_001127180.2:c.3862G>C

NM_001369365.1:c.3829G>C

Likely Pathogenic

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

PM3_Strong PP4 PP3 PM2_Supporting

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 NM_000260.4:c.3862G>C variant in the MYO7A gene is a missense variant predicted to cause substitution of alanine to proline at amino acid 1288 (p.Ala1288Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (7/110006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.833, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in five individuals with hearing loss or clinical features of Usher syndrome who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. However, for each individual phase was unknown (PMID: 10094549, 26969326, SCV001533246.2, 2.5 PM3 points) (PM3_Strong, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3_Strong, PM2_Supporting, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022)

PM3_Strong

This variant has been detected in five individuals with hearing loss or clinical features of Usher syndrome who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. However, for each individual phase was unknown (PMID: 10094549, 26969326, SCV001533246.2, 2.5 PM3 points) (PM3_Strong, PP4). 1) Invitae internal evidence - Ala1288Pro and p.Tyr403Cys phase unknown in 1 proband with Profound SNHL, prelingual, vestibular dysfunction, RP - 0.5pt PM3, PP4 2) Invitae internal Evidence - Phase unknown with c.2838del p.Met946Ilefs*116 (NMD+, 1/112084 alleles gnomAD, PM2_S met) dx of Usher syndrome (0.5 PM3, PP4) ****AO NOTE: double check the MAF! Which subpopulation? [update 1.01.2023, european non-finnish) 3) PMID:10094549 4 and 5) 26969326

PP4

Several individuals with features of Usher syndrome, See PM3 for details.

PP3

The computational predictor REVEL gives a score of 0.833, evidence that correlates with impact to MYO7A function (PP3).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (7/110006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting.

Curation History

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