ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.4027A>C (p.Asn1343His) (rs754634823)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666331 SCV000790604 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-10-09 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001004872 SCV001164353 uncertain significance Usher syndrome, type 2A 2018-12-03 criteria provided, single submitter research The homozygous p.Asn1343His variant in USH2A was identified by our study in one individual with Usher syndrome. The p.Asn1343His variant in USH2A has been reported in 2 individuals (1 South Asian, 1 unknown) with retinitis pigmentosa, a clinical feature of Usher syndrome (PMID: 28041643, 23591405), and has been identified in 0.07473% (23/30778) of South Asian chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754634823). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present, in a homozygous state, at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 438020). This variant was seen in combination with another USH2A variant, which has not been reported in ClinVar, in one individual with retinitis pigmentosaa (PMID: 23591405). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).
Blueprint Genetics RCV001073650 SCV001239201 uncertain significance Retinal dystrophy 2019-08-02 criteria provided, single submitter clinical testing
Invitae RCV001239324 SCV001412193 uncertain significance not provided 2019-09-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 1343 of the USH2A protein (p.Asn1343His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs754634823, ExAC 0.08%). This variant has been observed in an individual affected with autosomal recessive retinitis pigmentosa (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 438020). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504740 SCV000598809 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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