ClinVar Miner

Submissions for variant NM_000722.4(CACNA2D1):c.2751A>T (p.Gln917His) (rs145109446)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703640 SCV000832549 uncertain significance Brugada syndrome 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 917 of the CACNA2D1 protein (p.Gln917His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs145109446, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Brugada syndrome, who also carried a second missense variant (p.Asp550Tyr) in the CACNA2D1 gene (PMID: 20817017). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A functional study of the Gln917His and Asp550Tyr variants in CACNA2D1 reported that the combination of these two variants resulted in abnormal CACNA2D1 channel properties (PMID: 25527503).  The clinical significance of this finding 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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