ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.3643A>G (p.Lys1215Glu)

dbSNP: rs1476884019
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV002276495 SCV002564314 uncertain significance Developmental and epileptic encephalopathy, 42 2021-08-20 criteria provided, single submitter clinical testing The c.3643A>G (p.Lys1215Glu) variant identified in the CACNA1A gene substitutes a very well conserved Lysine for Glutamine at amino acid1215/2507 (exon 21/47) for transcript NM_001127222.2. CACNA1A is an alternatively spliced transcript with multiple isoforms, and this variant is also called c.3646A>G if annotated from transcript NM_001127221.2 (NP_001120693.1:p.Lys1216Glu). This variant is absent from gnomAD(v3.1.1) and found with low frequency ingnomAD(v2.1.1) (1 heterozygote, 0 homozygotes; allele frequency: 4.05e-6) suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms predict this variant to be Damaging (SIFT; score: 0.001) and Benign (REVEL; score:0.194) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Lys1215 residue is not within a mapped domain of CACNA1A (UniProtKB:O00555). Given the lack of compelling evidence for its pathogenicity, the c.3643A>G (p.Lys1215Glu) variant identified in the CACNA1A gene is reported as a Variant of Uncertain Significance.

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