Variant: NM_000260.4(MYO7A):c.5804T>C (p.Leu1935Pro)

CA278691

43298 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 1f484128-351e-49bd-a7a1-877c462ffac6

Approved on: 2020-06-24

Published on: 2020-06-29

HGVS expressions

NM_000260.4:c.5804T>C
NM_000260.4(MYO7A):c.5804T>C (p.Leu1935Pro)
NC_000011.10:g.77207350T>C
CM000673.2:g.77207350T>C
NC_000011.9:g.76918395T>C
CM000673.1:g.76918395T>C
NC_000011.8:g.76596043T>C
NG_009086.1:g.84086T>C
NG_009086.2:g.84105T>C
ENST00000409709.9:c.5804T>C
ENST00000670577.1:c.3631T>C
ENST00000409619.6:c.5657T>C
ENST00000409709.7:c.5804T>C
ENST00000458169.2:c.3230T>C
ENST00000458637.6:c.5690T>C
ENST00000481328.7:n.3340T>C
ENST00000605744.1:n.718T>C
NM_000260.3:c.5804T>C
NM_001127180.1:c.5690T>C
NM_001127180.2:c.5690T>C
NM_001369365.1:c.5657T>C

Likely Pathogenic

• Met criteria codes: PP3 PP4 PM3 PM2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.5804T>C (p.Leu1935Pro) variant in MYO7A is present in in 0.00236% (3/127394) of European (non-Finnish) chromosomes in gnomAD v2.1.1, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The variant has been detected in 1 patient with hearing loss in trans with the pathogenic c.1200+1G>A variant (PM3; Partners LMM internal data, SCV000059855.6). At least one patient with this variant displayed features of hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4; Blueprint Genetics internal data, SCV001239772.1). The REVEL computation prediction tool produced a score of 0.961, 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 the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP3, PP4).

Met criteria codes

• PP3: The REVEL score is 0.961, the residue is conserved across all vertebrates in the UCSC genome browser, and there is a possible 3' cryptic splice site creation predicted by MaxEntScan.
• PP4: Proband from Blueprint Genetics has hearing loss and RP.
• PM3: Present in one proband with severe to profound SNHL with delayed walking and balance issues in trans with the pathogenic c.1200+1G>A variant in MYO7A. No mention of RP but report mentions that the proband should be followed to see if the phenotype develops.
• PM2: Present in 0.00236% (3/127394) of European (non-Finnish) chromosomes in gnomAD v2.1.1 and in 0.00155% (1/64574) of European (non-Finnish) chromosomes in gnomAD v3.