Variant: NM_000260.4(MYO7A):c.631A>G (p.Ser211Gly)

x This classification has been retracted/unpublished!

CA278707

43325 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: fe99b50b-ba3f-4ebf-9816-12fa2f37b939

Approved on: 2020-05-06

Published on: 2020-05-12

HGVS expressions

NM_000260.4:c.631A>G
NM_000260.4(MYO7A):c.631A>G (p.Ser211Gly)
NC_000011.10:g.77156900A>G
CM000673.2:g.77156900A>G
NC_000011.9:g.76867946A>G
CM000673.1:g.76867946A>G
NC_000011.8:g.76545594A>G
NG_009086.1:g.33637A>G
NG_009086.2:g.33655A>G
ENST00000409709.9:c.631A>G
ENST00000409619.6:c.598A>G
ENST00000409709.7:c.631A>G
ENST00000409893.5:c.631A>G
ENST00000458637.6:c.631A>G
ENST00000620575.4:c.631A>G
NM_000260.3:c.631A>G
NM_001127179.2:c.631A>G
NM_001127180.1:c.631A>G
NM_001127180.2:c.631A>G
NM_001369365.1:c.598A>G

Likely Pathogenic

• Met criteria codes: PP3 PP4 PM2_Supporting PM3_Strong

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.631A>G (p.Ser211Gly) variant in MYO7A was present in 0.009% (6/64570) of non-Finnish European chromosomes in gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been observed in at least 3 probands with Usher syndrome who carried other pathogenic or likely pathogenic variants in MYO7A; in two cases the other variant was confirmed to be in trans (PM3_Strong; PMID: 25472526, LMM internal data, SCV000059882.6). All three of these probands displayed hearing loss and retinitis pigmentosa, features highly specific for MYO7A and Usher syndrome (PP4). The REVEL computational prediction analysis tool produced a score of 0.96, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2_Supporting, PM3_Strong, PP3, PP4).

Met criteria codes

• PP3: REVEL score 0.957. Alamut does not predict an impact to splicing. Entirely conserved in UCSC database.
• PP4: Both LMM probands and the published proband had a combination of SNHL and RP.
• PM2_Supporting: Present in 0.005453% (7/128370) of non-Finnish European chromosomes in gnomAD v2.1.1. Not present in any other subpopulations. In v3, present in 0.009292% (6/64570) of non-Finnish European chromosomes; also seen in 1 Latino chromosome.
• PM3_Strong: 1 published case and 2 from LMM, for 2.5 PM3 points total. Both LMM probands had likely pathogenic variants identified in trans.