Submissions for variant NM_001378969.1(KCND3):c.1798G>A (p.Gly600Arg)

gnomAD frequency: 0.00005  dbSNP: rs149344567

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619002	SCV000737719	likely benign	Cardiovascular phenotype	2023-07-18	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.
Athena Diagnostics	RCV000712060	SCV000842474	uncertain significance	not provided	2021-04-07	criteria provided, single submitter	clinical testing
Invitae	RCV001370775	SCV001567308	uncertain significance	Spinocerebellar ataxia type 19/22	2023-08-28	criteria provided, single submitter	clinical testing	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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 600 of the KCND3 protein (p.Gly600Arg). This variant is present in population databases (rs149344567, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 21349352, 22457051). ClinVar contains an entry for this variant (Variation ID: 192254). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCND3 function (PMID: 21349352, 22457051, 26016905).
GeneDx	RCV000712060	SCV001812577	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	Reported in at least one individual with Brugada syndrome and sudden unexplained death (PMID: 22457051); At the protein level, in silico analysis indicates that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Published functional studies suggest a damaging effect as this variant significantly increased peak current density and slowed transient outward current inactivation (PMID: 22457051); This variant is associated with the following publications: (PMID: 22840528, 29053796, 30662450, 22457051)
AiLife Diagnostics, AiLife Diagnostics	RCV000712060	SCV002503338	uncertain significance	not provided	2021-05-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505242	SCV002815249	uncertain significance	Spinocerebellar ataxia type 19/22; Brugada syndrome 9	2021-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000172843	SCV000223809	pathogenic	Brugada syndrome 9	2012-06-01	no assertion criteria provided	literature only