Variant: NM_000260.4(MYO7A):c.4115T>G (p.Val1372Gly)

CA353603

224749 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 580d30fb-1bb1-468a-bb63-1d786dac0556

Approved on: 2024-11-26

Published on: 2025-01-06

HGVS expressions

NM_000260.4(MYO7A):c.4115T>G
NM_000260.4:c.4115T>G
NM_000260.4(MYO7A):c.4115T>G (p.Val1372Gly)
NC_000011.10:g.77192241T>G
CM000673.2:g.77192241T>G
NC_000011.9:g.76903286T>G
CM000673.1:g.76903286T>G
NC_000011.8:g.76580934T>G
NG_009086.1:g.68977T>G
NG_009086.2:g.68996T>G
ENST00000409709.9:c.4115T>G
ENST00000670577.1:c.1956T>G
ENST00000409619.6:c.4082T>G
ENST00000409709.7:c.4115T>G
ENST00000458169.2:c.1658T>G
ENST00000458637.6:c.4115T>G
ENST00000481328.7:n.1658T>G
NM_000260.3:c.4115T>G
NM_001127180.1:c.4115T>G
NM_001127180.2:c.4115T>G
NM_001369365.1:c.4082T>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4 PP3 PM5_Supporting PM3

• Not Met criteria codes: BA1

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

Evidence submitted by expert panel

Hearing Loss VCEP

The c.4115T>G variant in MYO7A is a missense variant predicted to cause substitution of valine by glycine at amino acid 1372. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID: 31836858). A different missense variant in the same codon (c.4114G>A (p.Val1372Met), PMID: 33576163), has been reported in the homozygous state in a patient with hearing loss and retinitis pigmentosa. However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing loss VCEP (PM5_Supporting). In summary, this variant has been classified as a likely pathogenic variant for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP3, PP4, PM2_Supporting, PM5_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/26/2024).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PP4: At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858).
• PP3: The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3).
• PM5_Supporting: An individual with Usher syndrome was reported to be homozygous for a different missense variant at the same amino acid residue NM_000260.3(MYO7A):c.4114G>A(Val1372Met). PMID: 33576163.
• PM3: At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID: 31836858).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline