ClinVar Miner

Submissions for variant NM_000726.4(CACNB4):c.311G>T (p.Cys104Phe) (rs1805031)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487686 SCV000575234 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000186828 SCV000240399 uncertain significance not specified 2016-08-18 criteria provided, single submitter clinical testing p.Cys104Phe (TGC>TTC): c.311 G>T in exon 4 of the CACNB4 gene (NM_000726.2). The Cys104Phe missense substitution has been observed previously in a father and son with idiopathic generalized epilepsy (IGE) and in several individuals from a different family with episodic ataxia but no seizures (Escayg et al., 2000). This variant was not identified in 255 control individuals, indicating that it is not a common benign polymorphism. Functional studies also did not reveal any abnormalities in calcium channel kinetics as a result of the Cys104Phe substitution, hence providing no indication that this variant is pathogenic (Escayg et al., 2000). The amino acid change is non-conservative, as a polar Cysteine is replaced by a non-polar Phenylalanine, and the loss of a Cysteine residue may alter disulfide bond formation in the protein. It alters a position that is highly conserved in the CACNB4 protein and in related proteins. Some in silico models predict that Cys104Phe is damaging to protein structure/function, while others suggest it is likely benign. In summary, with the clinical and molecular information available at this time, it is unclear whether Cys104Phe is a disease-causing mutation or a rare, benign polymorphism. The variant is found in EPILEPSY,CHILD-EPI panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000298698 SCV000417250 likely benign Juvenile myoclonic epilepsy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000527001 SCV000632030 likely benign Idiopathic generalized epilepsy 2017-05-17 criteria provided, single submitter clinical testing
OMIM RCV000008046 SCV000028251 risk factor Epilepsy, idiopathic generalized 9 2000-05-01 no assertion criteria provided literature only
OMIM RCV000008047 SCV000028252 pathogenic Episodic ataxia, type 5 2000-05-01 no assertion criteria provided literature only

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