ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.6659C>A (p.Pro2220His)

dbSNP: rs16052
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001707709 SCV000590304 likely benign not provided 2021-01-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 15979945)
Invitae RCV000653344 SCV000775223 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2221 of the CACNA1A protein (p.Pro2221His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 432563). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV002367677 SCV002663850 uncertain significance Inborn genetic diseases 2018-01-19 criteria provided, single submitter clinical testing The p.P2221H variant (also known as c.6662C>A), located in coding exon 46 of the CACNA1A gene, results from a C to A substitution at nucleotide position 6662. The proline at codon 2221 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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