Variant: NM_000260.4(MYO7A):c.3827C>T (p.Ser1276Leu)

CA278732

178283 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 0e2cad56-a84e-46aa-b94f-6652a04eb450

Approved on: 2020-02-19

Published on: 2020-02-20

HGVS expressions

NM_000260.4:c.3827C>T
NM_000260.4(MYO7A):c.3827C>T (p.Ser1276Leu)
NC_000011.10:g.77190773C>T
CM000673.2:g.77190773C>T
NC_000011.9:g.76901818C>T
CM000673.1:g.76901818C>T
NC_000011.8:g.76579466C>T
NG_009086.1:g.67509C>T
NG_009086.2:g.67528C>T
ENST00000409709.9:c.3827C>T
ENST00000670577.1:c.1668C>T
ENST00000409619.6:c.3794C>T
ENST00000409709.7:c.3827C>T
ENST00000458169.2:c.1370C>T
ENST00000458637.6:c.3827C>T
ENST00000467137.1:n.354C>T
ENST00000481328.7:n.1370C>T
NM_000260.3:c.3827C>T
NM_001127180.1:c.3827C>T
NM_001127180.2:c.3827C>T
NM_001369365.1:c.3794C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3 PM3

• Not Met criteria codes: PP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the p.Ser1276Leu variant in the MYO7A gene is 0.008% (1/12706) of African chromosomes by 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 detected in 1 patient with hearing loss in trans with a likely pathogenic variant (PM3; Partners LMM internal data SCV000204707.4). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PP3, PM2_Supporting, PM3.

Met criteria codes

• PM2_Supporting: This variant was identified in 1/12706 African alleles in gnomAD (0.008%) which meets the cutoff for PM2_Supporting for AR disease.
• PP3: The REVEL score is 0.769, which is above the HL cutoff for pathogenicity 0.7. The residue is entirely conserved in UCSC and no species harbor the variant amino acid. Maxentscan does not predict any splicing differences.
• PM3: The variant was identified in an individual with mild hearing loss and retinal pigmentary changes. It was confirmed in trans with the p.Leu366Pro variant in MYO7A (LMM internal data SCV000204707.4). This variant is classified as LP with 2 star concordance by two clinical labs in ClinVar. This scores 1 point for PM3.

Not Met criteria codes

• PP4: The patient's phenotype (mild hearing loss with retinal pigment changes) is not necessarily consistent with Usher syndrome Type 1.