Variant: NM_000260.4(MYO7A):c.6326C>T (p.Thr2109Ile)

CA278724

164724 (ClinVar)

Gene: MYO7A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: a0970228-dea0-44d1-aa6d-d35746a8cff7

Approved on: 2019-11-26

Published on: 2019-11-26

HGVS expressions

NM_000260.4:c.6326C>T
NM_000260.4(MYO7A):c.6326C>T (p.Thr2109Ile)
NC_000011.10:g.77211909C>T
CM000673.2:g.77211909C>T
NC_000011.9:g.76922954C>T
CM000673.1:g.76922954C>T
NC_000011.8:g.76600602C>T
NG_009086.1:g.88645C>T
NG_009086.2:g.88664C>T
ENST00000409709.9:c.6326C>T
ENST00000670577.1:c.4127C>T
ENST00000409619.6:c.6179C>T
ENST00000409709.7:c.6326C>T
ENST00000458169.2:c.3752C>T
ENST00000458637.6:c.6212C>T
ENST00000481328.7:n.3862C>T
ENST00000526863.2:n.26-636C>T
ENST00000605744.1:n.1793C>T
NM_000260.3:c.6326C>T
NM_001127180.1:c.6212C>T
NM_001127180.2:c.6212C>T
NM_001369365.1:c.6179C>T

Likely Pathogenic

• Met criteria codes: PP1 PP3 PP4 PM2 PM3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.6326C>T (p.Thr2109Ile) variant in MYO7A is present in 8/128408 (0.00003% CI 95%) of European alleles in gnomAD (PM2). The variant has been detected in 2 probands with clinical features of Usher syndrome (PP4; SCV000199631.4). At least one proband displayed congenital progressive profound sensorineural hearing loss and retinitis pigmentosa, features of Usher syndrome (PP4; SCV000199631.4). In one proband, a pathogenic or suspected-pathogenic variant was observed in trans (VCV000043313.2). In the other proband, a variant of uncertain significance was observed in trans (VCV000178667.1; SCV000199631.4; PM3). Both probands had affected siblings in whom variants segregated (PP1). The REVEL computational prediction analysis tool produced a score of 0.821, 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, PP1, PP4).

Met criteria codes

• PP1: Variant and likely path/path variant (VCV000043313.2 ) segregated in one sibling with clinical features of Usher syndrome (SCV000199631.4).
• PP3: REVEL: .821
• PP4: Proband with congenital progressive profound sensorineural hearing loss and retinitis pigmentosa (SCV000199631.4).
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: Proband with clinical features of Usher syndrome carried the variant (VCV000043313.2) in trans with a likely path/path variant (SCV000199631.4). (1 PM3 pt.) Proband with congenital progressive profound sensorineural hearing loss and retinitis pigmentosa also carried a variant of uncertain significance (VCV000178667.1) in trans (SCV000199631.4). (.25 PM3 pts.)