ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.2823G>T (p.Lys941Asn) (rs773599066)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000372084 SCV000363176 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000279802 SCV000363177 uncertain significance Usher syndrome type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826011 SCV000967499 uncertain significance not specified 2018-08-08 criteria provided, single submitter clinical testing The p.Lys941Asn variant in PCDH15 has not been previously reported in individual s with hearing loss or Usher syndrome but has been identified in 0.03% (3/8728) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 300184). Computational prediction tools and conservation analysis suggest tha t the p.Lys941Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signific ance of the p.Lys941Asn variant is uncertain. ACMG/AMP Criteria applied: PP3, PM 2_Supporting.
Invitae RCV001051889 SCV001216071 uncertain significance not provided 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 941 of the PCDH15 protein (p.Lys941Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs773599066, ExAC 0.02%). This variant has not been reported in the literature in individuals with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 300184). 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: "Tolerated"; 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.

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