Variant: NM_206933.3(USH2A):c.11713C>T (p.Arg3905Cys)

CA1393629

236537 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 1358e892-e818-4d36-8c8f-962217401ae3

HGVS expressions

NM_206933.3:c.11713C>T
NM_206933.3(USH2A):c.11713C>T (p.Arg3905Cys)
NC_000001.11:g.215728383G>A
CM000663.2:g.215728383G>A
NC_000001.10:g.215901725G>A
CM000663.1:g.215901725G>A
NC_000001.9:g.213968348G>A
NG_009497.1:g.700014C>T
NG_009497.2:g.700066C>T
NM_206933.2:c.11713C>T
NM_206933.4:c.11713C>T
ENST00000307340.7:c.11713C>T

Likely Pathogenic

• Met criteria codes: PM3_Strong PM2_Supporting PP3 PP4

• Not Met criteria codes: PM5

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.11713C>T (p.Arg3905Cys) variant in USH2A was present in 0.03281% (1/3048) of South Asian chromosomes in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been reported in 3 individuals with Usher syndrome and a second pathogenic or likely pathogenic variant identified in USH2A, one of which was confirmed to be in trans with the p.Arg3905Cys variant (PM3_Strong; PMID: 28559085, 27208204, 31877679). At least one of these probands was confirmed to have both hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4). The REVEL computational prediction tool produced a score of 0.8, 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: PM3_Strong, PM2_Supporting, PP3, PP4.

Met criteria codes

• PM3_Strong: Observed in 4 probands with Usher syndrome with second pathogenic/likely pathogenic variants identified, one of which was confirmed to be in trans (PMID: 28559085, 27208204, 31877679, 24944099).
• PM2_Supporting: Present in 0.005026% (1/19896) of East Asian chromosomes in gnomAD v2. In v3, present in 0.03281% (1/3048) of South Asian chromosomes.
• PP3: REVEL score 0.8. Not predicted to impact splicing. Cys is present in 1 other mammal in UCSC database (golden hamster).
• PP4: 1 proband with Usher syndrome had audio-vestibular testing and opthalmological examination.

Not Met criteria codes

• PM5: One other variant in this codon, c.11714G>A (p.Arg3905His), is classified as VUS by 1 submitter only.

Approved on: 2020-06-24

Published on: 2020-06-26