ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.4072C>T (p.Arg1358Trp) (rs1555745461)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523450 SCV000616669 pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing The R1359W variant in the CACNA1A gene has been reported previously as de novo in an individual with epilepsy, ataxia, intellectual disability, and hypotonia (Ohba et al., 2013). The R1359W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1359W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1359W as a pathogenic variant
Athena Diagnostics Inc RCV000523450 SCV000841274 likely pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287223 SCV001473890 likely pathogenic none provided 2020-01-22 criteria provided, single submitter clinical testing
Clinical Genomics Program, Stanford Medicine RCV001252961 SCV001427033 likely pathogenic CACNA1A-associated disorders 2019-05-24 no assertion criteria provided clinical testing The p.Arg1359Trp variant in the CACNA1A gene has been previously reported de novo in two unrelated individuals, one individual with early onset epilepsy, ataxia, dysmetria, oculomotor apraxia, tremor, developmental delay, intellectual disability, speech delay, hypotonia, and pyramidal sign (Ohba et al., 2013), and one individual with an undescribed neurological condition (Nolan and Carlson, 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CACNA1A gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Arg1359Trp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg1359Trp variant as likely pathogenic for CACNA1A-assocatied disorders in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP2; PP3]

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