ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.3169C>T (p.Arg1057Cys) (rs187393245)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720827 SCV000851711 uncertain significance History of neurodevelopmental disorder 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000440421 SCV000526959 uncertain significance not specified 2016-04-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R1057C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports R1057C was observed in 4/208 (2.0%) alleles from individuals of Japanese background, indicating it may be a rare (benign) variant in this population. The R1057C 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 in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000553097 SCV000656744 benign Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2017-03-28 criteria provided, single submitter clinical testing

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