ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487686 SCV000575234 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing
Invitae RCV001081010 SCV000632030 likely benign Idiopathic generalized epilepsy 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000298698 SCV001135982 uncertain significance Juvenile myoclonic epilepsy 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000008047 SCV001288668 benign Episodic ataxia, type 5 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
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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