Variant: NM_206933.2(USH2A):c.11241C>A (p.Tyr3747Ter)

CA1393780

506273 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: b7a55bd1-1f82-499f-acdf-a7a6884c636c

HGVS expressions

NM_206933.2:c.11241C>A
NM_206933.2(USH2A):c.11241C>A (p.Tyr3747Ter)
NC_000001.11:g.215758743G>T
CM000663.2:g.215758743G>T
NC_000001.10:g.215932085G>T
CM000663.1:g.215932085G>T
NC_000001.9:g.213998708G>T
NG_009497.1:g.669654C>A
NM_206933.3:c.11241C>A
ENST00000307340.7:c.11241C>A

Pathogenic

• Met criteria codes: PM3_Supporting PM2_Supporting PVS1

• Not Met criteria codes: BS1 BS4 BS2 BP7 BP5 BP4 BP3 BP2 PM5 PM4 PM1 PM6 PS1 PS3 PS4 PS2 BA1 PP3 PP1 PP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The p.Tyr3747X variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 58/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Tyr3747X variant in the Ush2A gene is 0.017% (4/24020) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award 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 suspected pathogenic variant (PM3_Supporting, Partners LMM internal data SCV000713838.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Supporting.

Met criteria codes

• PM3_Supporting: Patient also has exon 63-64 deletion, phase not confirmed, but 63-64 del has been reported with other truncating variants (LMM internal data)
• PM2_Supporting: 4/24020 (0.00017) in Africans in gnomAD. Meets PM2_P
• PVS1: Predicted to undergo NMD (Exon 58/72 exons), exon is not alternately spliced

Not Met criteria codes

• BS1: 4/24020 (0.00017) in Africans in gnomAD. Meets PM2_P
• BS4: 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: 4/24020 (0.00017) in Africans in gnomAD. Meets PM2_P
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2018-09-17

Published on: 2019-07-17