Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_206933.3(USH2A):c.12295-3T>A

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CA143283

48395 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b99c4bbd-e16a-4f93-a065-1e6c947c7475

Approved on: 2019-10-23

Published on: 2019-10-23

HGVS expressions

NM_206933.3:c.12295-3T>A

NM_206933.3(USH2A):c.12295-3T>A

NC_000001.11:g.215675619A>T

CM000663.2:g.215675619A>T

NC_000001.10:g.215848961A>T

CM000663.1:g.215848961A>T

NC_000001.9:g.213915584A>T

NG_009497.1:g.752778T>A

NG_009497.2:g.752830T>A

ENST00000307340.8:c.12295-3T>A

ENST00000674083.1:c.12295-3T>A

ENST00000307340.7:c.12295-3T>A

NM_206933.2:c.12295-3T>A

NM_206933.4:c.12295-3T>A

Likely Pathogenic

PM3 PM2 PVS1_Strong PP4

BP7 PS3

Evidence Links 3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.12295-3T>A variant is present in 5/127918 (0.0039%) of European (non-Finnish) chromosomes in gnomAD (PM2). The variant has also been identified in 2 probands with hearing loss, one of whom was diagnosed with Usher syndrome and both probands also harbored the pathogenic p.Glu767Serfs*21 variant in USH2A (PM3, PP4). While this variant does not occur within the canonical splice site (±1,2), it has been shown to cause out-of-frame exon skipping in patient-derived cells and pathogenic variants in this exon have been reported in ClinVar (PVS1_Strong, PMID:25649381). 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 ClinGen Hearing Loss Expert Panel (PVS1_Strong, PM3, PM2, PP4).

PM3

Total of 6 cases (from publications and 1 from LMM internal data). LMM internal case did not have another variant but had profound sensorineural hearing loss with delayed walking so was not scored. Total of 1 point leads to a PM3 classification.

European male (35 yo) with nyctalopia, RP, and Group 3 audiology but no subjective hearing loss --> 0 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) European male (50 yo) with nyctalopia, RP, and Group 2 audiology but no subjective hearing loss --> 0.5 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) European male (54 yo) with nyctalopia and Group 1B audiology but no subjective hearing loss --> 0 points - other variant is c.12093C>A (p.Tyr4031*) PubMed:25649381

Indian proband diagnosed with Usher type 2 --> 0.5 points (phase unknown) - other variant is p.Glu767Serfs*21 PubMed:22135276

Proband with retinitis pigmentosa, no HL reported (onset 36 yo) - 0 points PubMed:25910913

PM2

The variant is present in 5/127918 (0.0039%) of European (non-Finnish) chromosomes in gnomAD, which meets the criteria to be assigned PM2.

PVS1_Strong

While this variant is not present in the canonical splice site, functional evidence indicates that the exon skipping occurs and it is not predicted to undergo NMD.

PP4

Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A. PubMed:22135276

BP7

The variant does not affect splicing using the MaxEntScan predictor but the nucleotide is relatively conserved (PhyloP: 4.16)

PS3

VCEP advised for evidence to be scored as PVS1 not PS3.

RT-PCR analysis of patient with c.12295-3T>A mutation showed a shorter product corresponding to skipping of USH2A exon 63, creating a premature stop codon. The patient also had another variant in USH2A, c.12093C>A and direct sequencing showed the variants are on different alleles (in trans). PubMed:25649381

Curation History

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