ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.6508C>T (p.Arg2170Cys) (rs375354077)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716497 SCV000847338 uncertain significance History of neurodevelopmental disorder 2016-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732133 SCV000860043 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764175 SCV000895177 uncertain significance Episodic ataxia type 2; Spinocerebellar ataxia 6; Familial hemiplegic migraine type 1; Epileptic encephalopathy, early infantile, 42 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000732133 SCV000571342 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R2170C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although theR2170C was not observed with any significant frequency in approximately 6,000 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencingreads and therefore may be unreliable. The R2170C variant is a non-conservative amino acid substitution, which islikely 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 isprobably damaging to the protein structure/function. However, missense variants in nearby residues have not beenreported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al.,2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenicvariant or a rare benign variant.
Invitae RCV000537075 SCV000656791 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2017-03-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2170 of the CACNA1A protein (p.Arg2170Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. While this variant is present in population databases (rs375354077), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CACNA1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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