VCV000192254.19 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 192254 Accession: VCV000192254.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p13.2 1: 111776247 (GRCh38) [ NCBI UCSC ] 1: 112318869 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 8, 2015	Jul 23, 2024	Jun 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378969.1:c.1798G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365898.1:p.Gly600Arg	missense
NM_001378970.1:c.1741G>A	NP_001365899.1:p.Gly581Arg	missense
NM_004980.5:c.1798G>A	NP_004971.2:p.Gly600Arg	missense
NM_172198.3:c.1741G>A	NP_751948.1:p.Gly581Arg	missense
NC_000001.11:g.111776247C>T
NC_000001.10:g.112318869C>T
NG_032011.2:g.217909G>A
LRG_445:g.217909G>A
LRG_445t1:c.1798G>A	LRG_445p1:p.Gly600Arg
	Q9UK17:p.Gly600Arg

... more HGVS ... less HGVS

Protein change

G581R

Other names

G600R

Canonical SPDI

NC_000001.11:111776246:C:T

Functional
consequence

The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele
frequency (GMAF)

The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency

The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00008

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA052108

UniProtKB: Q9UK17#VAR_067696

OMIM: 605411.0006

dbSNP: rs149344567

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KCND3		-	-	GRCh38 GRCh37	516	529

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Brugada syndrome 9	Pathogenic (1)	no assertion criteria provided	Jun 1, 2012	RCV000172843.11
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jul 18, 2023	RCV000619002.12
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jun 12, 2024	RCV000712060.16
Spinocerebellar ataxia type 19/22	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2023	RCV001370775.13
Brugada syndrome 9 Spinocerebellar ataxia type 19/22	Uncertain significance (1)	criteria provided, single submitter	Oct 30, 2021	RCV002505242.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 07, 2021)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000842474.2 First in ClinVar: Oct 20, 2018 Last updated: Sep 19, 2021	Publications: PubMed (11) PubMed: 23414114‚ 22457051‚ 21349352‚ 22336521‚ 23400760‚ 24762397‚ 25214526‚ 26016905‚ 22284586‚ 21640846‚ 22840528
Uncertain significance (May 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503338.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (4) PubMed: 22457051‚ 30662450‚ 22840528‚ 29053796 Number of individuals with the variant: 2 Secondary finding: no
Uncertain significance (Oct 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 19/22 Brugada syndrome 9 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002815249.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Spinocerebellar ataxia type 19/22 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001567308.4 First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 21349352‚ 22457051‚ 26016905 Comment: 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 … (more) 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). (less)
Likely benign (Jul 18, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000737719.6 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 21349352‚ 22284586‚ 22457051‚ 22840528‚ 23414114‚ 26016905‚ 29053796 Comment: 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 … (more) 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. (less)
Uncertain significance (Jun 12, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001812577.2 First in ClinVar: Sep 08, 2021 Last updated: Jul 23, 2024	Comment: 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 … (more) 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) (less)
Pathogenic (Jun 01, 2012)	no assertion criteria provided Method: literature only	BRUGADA SYNDROME 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000223809.2 First in ClinVar: Jun 08, 2015 Last updated: Jul 08, 2023	Publications: PubMed (3) PubMed: 21349352‚ 22457051‚ 26016905 Comment on evidence: In a 22-year-old man with Brugada syndrome (BRGDA9; 616399), Giudicessi et al. (2011) identified heterozygosity for a c.1798G-C transversion (later reported by Giudicessi et al. … (more) In a 22-year-old man with Brugada syndrome (BRGDA9; 616399), Giudicessi et al. (2011) identified heterozygosity for a c.1798G-C transversion (later reported by Giudicessi et al. (2012) as a c.1798G-A transition) in the KCND3 gene, resulting in a gly600-to-arg (G600R) substitution at a highly conserved residue in the Kv4.3 C terminus. The mutation was not found in 1,560 reference alleles. Functional analysis in HEK293 cells showed significantly increased transient outward current density at 0 mV and at 40 mV with the G600R mutant, by 48.1% and 50.4% over wildtype. In addition, the G600R mutant exhibited significantly slower inactivation across the 0 to 40 mV range and a significantly increased total charge of the transient outward current at 40 mV compared to wildtype. Using DNA from a 23-year-old asymptomatic male athlete who died from cardiopulmonary arrest while swimming laps, Giudicessi et al. (2012) identified heterozygosity for the G600R substitution in the KCND3 gene. The variant (rs149344567) was not found in 1,560 reference alleles or in the 1000 Genomes Project database; it was found in a single individual in the dbSNP (build 134) database. Premortem electrocardiograms (ECGs) from the proband were unavailable. There was no family history of sudden unexplained death, and screening ECGs in his parents and sister were reportedly normal. Family members declined to provide DNA for genetic testing. Functional analysis in HEK293 cells confirmed the marked gain-of-function electrophysiologic phenotype with the G600R variant. You et al. (2015) generated rat Kv4.3 with either a G581R or L450F mutation, corresponding to the human G600R and L450F (605411.0005) mutations associated with Brugada syndrome, respectively. Expression of mutant Kv4.3 with Kchip2 in HEK293 cells showed that the mutants caused a gain of function of the transient outward K+ currents, as the mutants increased Kv4.3 protein expression and influenced the kinetics of the transient outward K+ currents by slowing down channel inactivation. Furthermore, the Kv4.3 mutants enhanced membrane localization of the Kv4.3 protein, but they did not affect the mRNA level of Kv4.3. (less)

Comment:

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).

Comment:

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.

Comment:

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)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry.	Chen CJ	Frontiers in genetics	2019	PMID: 30662450
Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.	Nibbeling EAR	Brain : a journal of neurology	2017	PMID: 29053796
Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function.	You T	International journal of molecular medicine	2015	PMID: 26016905
Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death.	Perrin MJ	Circulation. Cardiovascular genetics	2014	PMID: 25214526
The potential role of Kv4.3 K+ channel in heart hypertrophy.	Huo R	Channels (Austin, Tex.)	2014	PMID: 24762397
High prevalence of genetic variants previously associated with Brugada syndrome in new exome data.	Risgaard B	Clinical genetics	2013	PMID: 23414114
A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation.	Olesen MS	Cardiovascular research	2013	PMID: 23400760
Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing.	Crotti L	Journal of the American College of Cardiology	2012	PMID: 22840528
Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.	Giudicessi JR	Human mutation	2012	PMID: 22457051
Distinguishing pathogenic mutations from innocuous rare variants in gene discovery for Brugada syndrome.	Roberts JD	The Canadian journal of cardiology	2012	PMID: 22336521
Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.	Holst AG	The Canadian journal of cardiology	2012	PMID: 22284586
KCND3 mutations in Brugada syndrome: the plot thickens.	van den Berg MP	Heart rhythm	2011	PMID: 21640846
Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.	Giudicessi JR	Heart rhythm	2011	PMID: 21349352
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Text-mined citations for rs149344567 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149344567 ...