ClinVar Miner

Submissions for variant NM_004980.4(KCND3):c.1174G>A (p.Val392Ile) (rs786205867)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000444260 SCV000521303 likely pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing A likely pathogenic variant was identified in the KCND3 gene. The V392I variant has been reported in a 20-year-old Caucasian male with SUD and a history of two syncopal episodes (Giudicessi et al., 2012). For that individual, no premortem ECG was available and familial segregation studies were declined, though parents and a sister had normal ECGs (Giudicessi et al., 2012). The V392I variant was not observed in approximately 6,500 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 V392I is a conservative amino acid substitution, which is less likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and two of three in silico algorithms predict it is probably damaging to protein structure/function. Furthermore, Giudicessi et al. (2012) performed functional characterization of V392I, which demonstrated significantly increased peak current density compared to wild type as well as slowed recovery from inactivation, suggestive of a mixed electrophysiological phenotype.Therefore, based on the evidence currently available this variant is classified as likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000460804 SCV000548726 uncertain significance Spinocerebellar ataxia 19 2016-09-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 392 of the KCND3 protein (p.Val392Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency) . This variant was reported in a sudden unexplained death case (PMID: 22457051) ClinVar contains an entry for this variant (Variation ID: 192255). In an experimental study, this variant was shown to result in increased potassium currents across the channel and slow down recovery (PMID: 22457051). However, the clinical significance of this finding is unclear. In summary, this is a rare variant with some evidence of a deleterious functional effect. For these reasons, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000172844 SCV000223810 pathogenic Brugada syndrome 9 2012-06-01 no assertion criteria provided literature only

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