ClinVar Miner

Submissions for variant NM_000720.4(CACNA1D):c.1208G>A (p.Gly403Asp)

dbSNP: rs386834264
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122469 SCV002235250 pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 403 of the CACNA1D protein (p.Gly403Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1D-related conditions (PMID: 23913001, 28318089). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66072). 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 expected to disrupt CACNA1D protein function. Experimental studies have shown that this missense change affects CACNA1D function (PMID: 23913001). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics RCV000122469 SCV002817245 pathogenic not provided 2020-06-10 criteria provided, single submitter clinical testing This variant occurs de novo in this current individual and in published literature (PMID: 28318089, 23913001). Assessment of experimental evidence suggests this is gain-of-function variant (PMID: 23913001).This variant has not been reported in large, multi-ethnic general populations ( observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
OMIM RCV000056307 SCV000087476 pathogenic Aldosterone-producing adenoma with seizures and neurological abnormalities 2013-09-01 no assertion criteria provided literature only
Richard Lifton Laboratory, Yale University School of Medicine RCV000122469 SCV000154977 probable-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia RCV000056307 SCV000238465 likely pathogenic Aldosterone-producing adenoma with seizures and neurological abnormalities 2015-01-14 no assertion criteria provided research The variant (c.1208G>A) is likely pathogenic because it was previously reported as a de novo alteration in a patient with primary aldosteronism, seizures, and global developmental delays (Scholl et al. 2013, PMID: 23913001). Electrophysiological study of this variant showed that it was comparable to a different mutation at amino acid position 403 (p.Gly403Arg) found in an adrenal aldosterone-producing adenoma that is activated at less depolarizing potentials and impairs the inactivation of the wildtype allele (Scholl et al. 2013, PMID: 23913001). This variant does not occur in ExAC 0.3 even though this genomic region is well-covered.

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