Variant: NM_206933.3(USH2A):c.9433C>T (p.Leu3145Phe)

CA1394316

73556 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: bdb45e0a-901a-41b7-8774-f1f4723b74c7

HGVS expressions

NM_206933.3:c.9433C>T
NM_206933.3(USH2A):c.9433C>T (p.Leu3145Phe)
NM_206933.2:c.9433C>T
NM_206933.4:c.9433C>T
ENST00000307340.7:c.9433C>T
NC_000001.11:g.215817134G>A
CM000663.2:g.215817134G>A
NC_000001.10:g.215990476G>A
CM000663.1:g.215990476G>A
NC_000001.9:g.214057099G>A
NG_009497.1:g.611263C>T
NG_009497.2:g.611315C>T

Uncertain Significance

• Met criteria codes: PM2 PM3_Supporting

• Not Met criteria codes: PP3 PP4 BP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.9433C>T (p.Leu3145Phe) variant in USH2A is present in 0.0033% (1/30612) of South Asian allele in gnomAd v2.1.1 and in 0.0074% (1/13568) of Latino alleles in gnomAD v3 (PM2). This variant has been detected in 1 proband with bilateral sensorineural hearing loss in a homozygous state (PM3_Supporting, PMID: 26806561). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3_Supporting.

Met criteria codes

• PM2: Present in 0.00327% (1/30612) of South Asian chromosomes in gnomAD v2.1.1 and in 0.00737% (1/13568) of Latino chromosomes in v3
• PM3_Supporting: Proband from Perez-Carro 2016 given 0.5 PM3 points to meet this criteria code at the supporting level.

Not Met criteria codes

• PP3: L3145 not highly conserved in UCSC (Val present in mouse, rat, ferret, panda, walrus, and more and Ile present in rabbit and elephant shrew)
• PP4: Proband in Perez-Carro 2016 had RP and bilateral SNHL, which are features highly specific for Usher syndrome and USH2A variants. Because the age of onset for the hearing loss was not reported, the group did not feel comfortable assigning the PP4 code.
• BP4: L3145 not highly conserved in UCSC (Val present in mouse, rat, ferret, panda, walrus, and more and Ile present in rabbit and elephant shrew)

Approved on: 2020-07-28

Published on: 2020-07-28