Evidence Repository
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

CA143283

48395 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b99c4bbd-e16a-4f93-a065-1e6c947c7475
Approved on: 2022-10-31
Published on: 2023-02-06

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
NM_206933.4(USH2A):c.12295-3T>A
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Pathogenic

Met criteria codes 4
PVS1_Strong PM2_Supporting PP4 PM3_Strong
Not Met criteria codes 2
BP7 PS3

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.12295-3T>A variant in USH2A is an intronic variant located within the acceptor splice consensus sequence of intron 62. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000039 (5/127918 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant has been identified in 4 individuals with clinical features or diagnosis of Usher syndrome with hearing loss (PMID: 25649381, 22135276; PP4). Three of these individuals were compound heterozygous, phase unknown, with the pathogenic p.Glu767Serfs*21 USH2A variant. The fourth individual harbored the Tyr4031* variant in USH2A, which was likely in trans as shown through RT-PCR sequencing (PM3_Strong). 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 pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PVS1_Strong, PM3_Strong, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022).
Met criteria codes
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.
PM2_Supporting
The variant is present in 0.0039% (5/127918) European chromosomes (non-Finnish) chromosomes in gnomAD, which meets the criteria to be assigned PM2_Supporting.
PP4
Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A. PubMed:22135276
PM3_Strong
10/2022 NOTES: We re-reviewed the literature and counted all three individuals from PMID: 25649381 (2x0.5pt for phase unknown, 1pt for phase determined vie RT PCR sequencing. The fourth individual from PMID: 22135276, phase unknown. Total of 2.5 points 10/2019 NOTES: 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
Proband with retinitis pigmentosa, no HL reported (onset 36 yo) - 0 points PubMed:25910913
Indian proband diagnosed with Usher type 2 --> 0.5 points (phase unknown) - other variant is p.Glu767Serfs*21 PubMed:22135276
Not Met criteria codes
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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