The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000260.4(MYO7A):c.401T>A (p.Ile134Asn)

CA278663

43230 (ClinVar)

Gene: MYO7A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 28c29ee7-31d4-4833-afbd-15bf5b29aa05
Approved on: 2024-09-18
Published on: 2024-09-30

HGVS expressions

NM_000260.4:c.401T>A
NM_000260.4(MYO7A):c.401T>A (p.Ile134Asn)
NC_000011.10:g.77156022T>A
CM000673.2:g.77156022T>A
NC_000011.9:g.76867068T>A
CM000673.1:g.76867068T>A
NC_000011.8:g.76544716T>A
NG_009086.1:g.32759T>A
NG_009086.2:g.32777T>A
ENST00000409709.9:c.401T>A
ENST00000409619.6:c.368T>A
ENST00000409709.7:c.401T>A
ENST00000409893.5:c.401T>A
ENST00000458637.6:c.401T>A
ENST00000620575.4:c.401T>A
NM_000260.3:c.401T>A
NM_001127179.2:c.401T>A
NM_001127180.1:c.401T>A
NM_001127180.2:c.401T>A
NM_001369365.1:c.368T>A
More

Pathogenic

Met criteria codes 5
PM3_Very Strong PP4 PP1 PP3 PM2_Supporting

Evidence Links 0

Expert Panel

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.401T>A (p.Ile134Asn) is a missense variant in MYO7A predicted to cause a substitution of isoleucine to asparagine at amino acid 134. The filtering allele frequency (the lower threshold of the 95% CI of 60/1179894) of this variant is 0.004019% in the European (non-Finnish) population which meets the threshold (≤0.00007, 0.007%) defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction tool produced a score of 0.938, which is above the threshold necessary to apply PP3 (PP3). This variant has been detected in 7 probands with Usher syndrome. For 2 of those probands, pathogenic variants (c.19-1G>A and p.Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown phase (4.5 points, PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM Internal Data ClinVar SCV000059786.6). At least one patient with this variant displayed features of sensorineural hearing loss and retinitis pigmentosa, which are consistent for Usher syndrome, a condition highly specific for MYO7A (PP4, Partners LMM Internal Data ClinVar SCV000059786.6). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel (PM3_Very Strong, PM2_Supporting, PP1, PP3, PP4). (ClinGen Hearing Loss VCEP specifications version 2; 9/18/2024).
Met criteria codes
PM3_Very Strong
A total of 4.5 PM3 points lead to a very strong classification. 7 probands with Usher syndrome were include in this curation. For 2 of those probands, pathogenic variants (c.19-1G>A and Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown and/or unspecified phase (PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6).
PP4
The 2 sisters both had SNHL and RP, which are highly specific for Usher syndrome.
PP1
2 sisters from LMM segregated with two MYO7A variants.
PP3
The REVEL score is 0.938 and there is no impact to splicing. The residue is conserved in all vertebrates in the UCSC browser.
PM2_Supporting
The Grpmax FAF in gnomAD v4.1 is 0.004019% in the European (non-Finnish) population which is below the threshold defined by the ClinGen HL EP for PM2 Supporting ( ≤0.00007 (0.007%)) for autosomal recessive conditions (PM2_S)
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.
¤ Powered by BCM's Genboree.