ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.4892C>A (p.Ala1631Glu) (rs56332160)

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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 RCV000319902 SCV000363132 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000386024 SCV000363133 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000845 SCV001157917 uncertain significance not specified 2018-12-19 criteria provided, single submitter clinical testing The PCDH15 c.4892C>A; p.Ala1631Glu variant (rs56332160), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 300175). This variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (23/126698 alleles) in the Genome Aggregation Database. The alanine at codon 1631 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ala1631Glu variant is uncertain at this time.
Invitae RCV001049538 SCV001213594 uncertain significance not provided 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 1631 of the PCDH15 protein (p.Ala1631Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs56332160, ExAC 0.02%). This variant has not been reported in the literature in individuals with PCDH15-related disease. ClinVar contains an entry for this variant (Variation ID: 300175). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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