ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.1256A>G (p.Asn419Ser) (rs143827620)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151635 SCV000199867 likely benign not specified 2014-09-29 criteria provided, single submitter clinical testing p.Asn419Ser variant in exon 11 of PCDH15: This variant is not expected to have c linical significance because it has been identified in 0.136% (6/4406) of Afric an American chromosomes by the NHLBI Exome Sequencing Project, and in 1.639% (2/ 122) of African American chromosomes and in 0.568% (1/176) of Nigerian chromosom es by the 1000 Genomes Project (; dbSNP rs14382 7620). In addtion, asparaginine (Asn) at position 419 is not well conserved in m ammals or evolutionarily distant species with many fish carrying a serine (Ser) at this position and computational prediction tools do not suggest a high likeli hood of impact to the protein. which supports that variants at this position may be tolerated.
Invitae RCV001071653 SCV001236967 uncertain significance not provided 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 419 of the PCDH15 protein (p.Asn419Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs143827620, ExAC 0.1%). This variant has not been reported in the literature in individuals with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 164927). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Illumina Clinical Services Laboratory,Illumina RCV001103156 SCV001259877 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.

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