ClinVar Miner

Submissions for variant NM_004320.5(ATP2A1):c.2774dup (p.Met925fs) (rs398124555)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082698 SCV000114742 pathogenic not provided 2014-04-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000381455 SCV000396407 uncertain significance Brody myopathy 2018-03-15 criteria provided, single submitter clinical testing The ATP2A1 c.2774dupT (p.Met925IlefsTer27) variant results in a frameshift and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Met925IlefsTer27 variant is reported at a frequency of 0.000134 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on only two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, the p.Met925IlefsTer27 variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Brody myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000082698 SCV000567264 pathogenic not provided 2015-08-07 criteria provided, single submitter clinical testing The c.2774dupT duplication in the ATP2A1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.2774dupT duplication causes a frameshiftstarting with codon Methionine 925, changes this amino acid to a Isoleucine residue, and creates apremature Stop codon at position 27 of the new reading frame, denoted p.Met925IlefsX27. This variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediatedmRNA decay. The c.2774dupT duplication was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. We interpret c.2774dupT as a pathogenic variant.

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