ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.4105T>C (p.Cys1369Arg) (rs886041909)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000317331 SCV000330709 pathogenic not provided 2016-07-20 criteria provided, single submitter clinical testing The C1369R pathogenic variant in the CACNA1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. A variant at the same residue, C1369Y (also reported as C1370Y due to alternate nomenclature), has been reported in an individual with tremor of the head and hands, epilepsy, migraine without aura, and cerebellar atrophy (Geerlings et al., 2011). The C1369Y variant was also reported in a family with familial hemiplegic migraine. However, the variant did not completely segregate with disease in the family, as the variant was only present in 3 out of 4 affected individuals (Thomsen et al., 2007). The C1369R variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C1369R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C1369R as a pathogenic variant.
Invitae RCV000802158 SCV000941976 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 1369 of the CACNA1A protein (p.Cys1369Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 280762). 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 disruptive, 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.

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