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Variant: NM_206933.3(USH2A):c.5857+2T>C

CA262109

48544 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 8eb3ee78-6625-4a84-bebc-eff570d0c2fc
Approved on: 2019-10-29
Published on: 2019-10-31

HGVS expressions

NM_206933.3:c.5857+2T>C
NM_206933.3(USH2A):c.5857+2T>C
NC_000001.11:g.216072887A>G
CM000663.2:g.216072887A>G
NC_000001.10:g.216246229A>G
CM000663.1:g.216246229A>G
NC_000001.9:g.214312852A>G
NG_009497.1:g.355510T>C
NM_206933.2:c.5857+2T>C
NR_125992.1:n.136+287A>G
NR_125993.1:n.136+287A>G
ENST00000307340.7:c.5857+2T>C

Likely Pathogenic

Met criteria codes 4
PP4 PVS1_Moderate PM2_Supporting PM3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.5857+2T>C variant in USH2A has been identified in at least 3 probands with Usher syndrome, including two who were compound heterozygous for a second pathogenic variant though phase was not confirmed (PM3, PP4; PMID 20507924, 20507924, 18641288, LMM unpublished data SCV000065566.6). The allele frequency of this variant is 0.01% (2/15422) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing, though the exact impact is unknown. Exon 29 is in-frame, and if the variant results in exon skipping, it would remove <10% of the USH2A protein. However, two truncating pathogenic / likely pathogenic variants in this exon have been reported in ClinVar, which may suggest it is required for normal protein function (PVS1_Moderate). 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 Hearing Loss Expert Panel (PVS1_Moderate, PM3, PP4, PM2_Supporting).
Met criteria codes
PP4
2 probands with Usher syndrome (Sandberg 2008 18641288 and LMM Unpublished data).

PVS1_Moderate
his variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing, though the exact impact is unknown. Exon 29 is in frame, and if the variant results in exon skipping, it would remove <10% of the USH2A protein. Two pathogenic / likely pathogenic variants in this exon have been reported in ClinVar, which may suggest it is required for normal protein function (PVS1_Moderate).
PM2_Supporting
The allele frequency of this variant is 0.01% (2/15422) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting).
PM3
he c.5857+2T>C variant in USH2A has been identified in at least 3 probands with Usher syndrome, including two who were compound heterozygous for a second pathogenic variant though phase was not confirmed (PM3, PP4; PMID 20507924, 20507924, 18641288, LMM unpublished data RCV000041870). LMM proband was compound het (phase not confirmed for c.5001_5002insA (p.Gly1668ArgfsX30.

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