Variant: NM_206933.2(USH2A):c.12505A>G (p.Thr4169Ala)

CA179513

166435 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 67f5ff79-03db-45e0-a679-81f69e505882

HGVS expressions

NM_206933.2:c.12505A>G
NM_206933.2(USH2A):c.12505A>G (p.Thr4169Ala)
NC_000001.11:g.215675406T>C
CM000663.2:g.215675406T>C
NC_000001.10:g.215848748T>C
CM000663.1:g.215848748T>C
NC_000001.9:g.213915371T>C
NG_009497.1:g.752991A>G
NM_206933.3:c.12505A>G
ENST00000307340.7:c.12505A>G

Likely Benign

• Met criteria codes: BP4 BS1

• Not Met criteria codes: PP3 PP4 BA1 BS2

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the p.Thr4169Ala variant in the USH2A gene is 0.32% for African chromosomes by gnomAD (82/24940 with 95% CI) (BS1). Computational predictors for the variant suggest no impact on the gene or gene product (REVEL score: 0.207) (BP4). Of note, this variant was reported in 4 patients with Usher syndrome (PMID:28041643) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS1 and BP4

Met criteria codes

• BP4: REVEL score: 0.207, PolyPhen2: benign, SIFT prediction: tolerated (in Alamut), MAPP Prediction: good. FATHMM: tolerated. Also present in 2 animals: cat and coelacanth.
• BS1: Present in 82/24940 (0.33%) of African alleles in gnomAD

Not Met criteria codes

• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-02-25

Published on: 2019-10-18