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  • See Evidence submitted by expert panel for details.

Variant: NM_206933.3(USH2A):c.12574C>T (p.Arg4192Cys)

CA1393449

281818 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 2c4d6b60-7250-4f03-8de9-0d25373a1521
Approved on: 2020-01-21
Published on: 2020-01-22

HGVS expressions

NM_206933.3:c.12574C>T
NM_206933.3(USH2A):c.12574C>T (p.Arg4192Cys)
NC_000001.11:g.215675337G>A
CM000663.2:g.215675337G>A
NC_000001.10:g.215848679G>A
CM000663.1:g.215848679G>A
NC_000001.9:g.213915302G>A
NG_009497.1:g.753060C>T
NG_009497.2:g.753112C>T
ENST00000307340.8:c.12574C>T
ENST00000674083.1:c.12574C>T
ENST00000307340.7:c.12574C>T
NM_206933.2:c.12574C>T
NM_206933.4:c.12574C>T
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Uncertain Significance

Met criteria codes 4
PP4 PM3 PM2_Supporting BP2
Not Met criteria codes 2
PP3 PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.12574C>T (p.Arg4192Cys) variant in USH2A is present in 0.007055% (9/127578) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). This variant was observed in at least 3 probands with Usher syndrome, including one individual with a suspected pathogenic missense variant in trans and another with a suspected pathogenic nonsense variant with phase unknown (PMID: 24516651, 27460420). At least one of these patients was clinically evaluated and confirmed to have both sensorineural deafness and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID: 27460420). However, a third proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (BP2; PMID: 29912909). Of note, this variant has been observed in several other probands presenting with retinitis pigmentosa without hearing loss. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: BP2, PM2_P, PM3, PP4.
Met criteria codes
PP4
1 proband was clinically evaluated and confirmed to have both sensorineural hearing loss and retinitis pigmentosa (PMID: 27460420).

PM3
Observed in 2 individuals with Usher syndrome who also carried P/LP variants in USH2A, 1 known in trans and the other with phase unknown (PMID: 24516651, 27460420).

PM2_Supporting
Present in 0.007055% (9/127578) of non-Finnish European chromosomes in gnomAD v2. In v3, present in 0.004759% (2/42022) of non-Finnish European chromosomes.
BP2
Observed in cis with p.Cys759Phe, P/LP in ClinVar by 15 submitters. However, both missense variants were in trans with the p.Thr2812Metfs*17 variant.

Not Met criteria codes
PP3
REVEL score 0.599. Splicing not predicted to be impacted using Alamut. Only 1 mammal (hedgehog) carries R>C substitution at this site.
PM5
1 other variant in ClinVar (R4192H). Population data and computational predictors indicate that it is benign, however there are conflicting interpretations of pathogenicity. Only 1 assertion in HGMD for this variant is for Usher syndrome, and another variant in the gene was not identified in this family.
Curation History
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