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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

Pathogenic

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

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
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
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
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.
Not Met criteria codes
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
BP7
The variant does not affect splicing using the MaxEntScan predictor but the nucleotide is relatively conserved (PhyloP: 4.16)
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