ClinVar Miner

Submissions for variant NM_000726.4(CACNB4):c.8C>T (p.Ser3Phe) (rs542973906)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186842 SCV000240413 uncertain significance not provided 2014-12-31 criteria provided, single submitter clinical testing p.Ser3Phe (TCC>TTC): c.8 C>T in exon 1 of the CACNB4 gene (NM_000726.2). The S3F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S3F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species in the N-terminal region of the CACNB4 protein. Additionally, to date only a small number of substitutions in CACNB4 have been published in association with epilepsy, and no disease-associated mutations have been reported in the N-terminal region of the protein (Excayg et al., 2000; Ohmori et al., 2008). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000321619 SCV000417259 likely benign Juvenile myoclonic epilepsy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000376086 SCV000417260 likely benign Episodic ataxia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000526121 SCV000632033 uncertain significance Idiopathic generalized epilepsy 2017-06-13 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 3 of the CACNB4 protein (p.Ser3Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs542973906, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a CACNB4-related disease. ClinVar contains an entry for this variant (Variation ID: 204938). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on CACNB4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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