ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.457G>A (p.Asp153Asn) (rs747856983)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586011 SCV000236204 uncertain significance not provided 2013-03-05 criteria provided, single submitter clinical testing p.Asp153Asn (GAC>AAC): c.457 G>A in exon 3 of the PKP2 gene (NM_004572.3) The Asp153Asn variant in the PKP2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp153Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved in most mammalian species. Mutations in nearby codons (Ser140Phe, Arg158Lys) have been reported in association with ARVC, supporting the functional importance of this region of the protein. The Asp153Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, in silico analysis predicts Asp153Asn is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Asp153Asn is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586011 SCV000698477 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.457G>A (p.Asp153Asn) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). The variant is located outside of some of the known domains/repeats in PKP2 protein (UniPro, InterPro). This variant was found in 1/121226 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301). One clinical diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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