Submissions for variant NM_001378969.1(KCND3):c.641A>G (p.Lys214Arg)

gnomAD frequency: 0.00034  dbSNP: rs142744204

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208485	SCV000263968	likely benign	not specified	2014-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000249346	SCV000320287	likely benign	Cardiovascular phenotype	2023-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558965	SCV000640063	uncertain significance	Spinocerebellar ataxia type 19/22	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 214 of the KCND3 protein (p.Lys214Arg). This variant is present in population databases (rs142744204, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atrial fibrillation, an episodic gait disorder or Brugada syndrome (PMID: 21349352, 22402074, 25410959, 26220970, 29482223). ClinVar contains an entry for this variant (Variation ID: 222665). 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 not expected to disrupt KCND3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001555788	SCV001777255	likely benign	not provided	2021-06-17	criteria provided, single submitter	clinical testing	Reported in a patient with features of cerebellar ataxia referred for whole exome sequencing; however, this variant was inherited from an unaffected mother (Coutelier et al., 2018); Reported in one ostensibly healthy control individual and in association with atrial fibrillation (Giudicessi et al., 2011; Mann et al., 2012); Published functional studies demonstrate no damaging effect (Mann et al., 2012); This variant is associated with the following publications: (PMID: 26220970, 23838598, 25175087, 25410959, 29482223, 22402074, 21349352)
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000558965	SCV003803728	uncertain significance	Spinocerebellar ataxia type 19/22		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001555788	SCV001927243	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001555788	SCV001973320	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737334	SCV005357153	uncertain significance	KCND3-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The KCND3 c.641A>G variant is predicted to result in the amino acid substitution p.Lys214Arg. This variant has been reported in individuals with episodic gait disorder, Brugada syndrome, or atrial fibrillation (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Mann SA et al 2012. PubMed ID: 22402074). However, this variant was also inherited from an unaffected parent of a proband with episodic gait disorder and was identified in controls for the Brugada syndrome study (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Giudicessi JR et al 2011. PubMed ID: 21349352). An in vitro study of this variant showed no change in cellular electrophysiology (Mann SA et al 2012. PubMed ID: 22402074). This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of autosomal dominant disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.