rs786205867

Variant names:

• chr1-111787039-C-T
• rs786205867
• NM_001378969.1:c.1174G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_001378969.1(KCND3):​c.1174G>A​(p.Val392Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 7.91
• Publications: 20 publications found

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

KCND3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• spinocerebellar ataxia type 19/22

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• Brugada syndrome 9

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124904312 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001378969.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCND3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.8545 (above the threshold of 3.09). Trascript score misZ: 4.8782 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 19/22, neurodevelopmental disorder, Brugada syndrome 1, Brugada syndrome 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 1-111787039-C-T is Pathogenic according to our data. Variant chr1-111787039-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1174G>A	p.Val392Ile	missense_variant	Exon 3 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1174G>A	p.Val392Ile	missense_variant	Exon 3 of 8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1174G>A	p.Val392Ile	missense_variant	Exon 3 of 8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1174G>A	p.Val392Ile	missense_variant	Exon 2 of 6	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 9 Pathogenic:2 Uncertain:1

Jun 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 07, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The KCND3 c.1174G>A variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE (PS4_Supporting, PM2, PP3) The KCND3 c.1174G>A variant is a single nucleotide change in exon 3/8 of the KCND3 gene, which is predicted to change the amino acid valine at position 392 in the protein to isoleucine. This variant has been reported as a de novo change in a 5yo boy with seizures, psychomotor regression and vision impairment (PMID:30776697) (PS4_Supporting). This variant has been reported in dbSNP (rs786205867) but is absent from population databases (PM2). This variant has been reported as pathogenic, likely pathogenic and VUS by other diagnostic laboratories (ClinVar Variation ID: 192255). it has also been reported as damaging in the HGMD disease database for Epileptic encephalopathy, Brugada syndrome and sudden unexplained death syndrome (CM124831). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Oct 02, 2021

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individual and observed (PMID: 30776697, PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.836, 3Cnet: 0.893, PP3). Patient's phenotype is considered compatible with KCND3-related seizure disorder.Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Nov 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in a 20-year-old male with SUD and a history of two syncopal episodes; however, no premortem ECG was available and familial segregation studies were declined (PMID: 22457051); Published functional studies demonstrated p.(V392I) significantly increased peak current density compared to wild type and slowed recovery from inactivation, suggestive of a mixed electrophysiological phenotype (PMID: 22457051); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23400760, 34426522, 34361012, 30662450, 32921676, 32901917, 30776697, 34709746, Ahammed2023[Review], 36376730, 33920294, 35861988, 35388935, 35813061, 22457051) -

May 08, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 19/22 Pathogenic:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant KCND3-related conditions and/or sudden unexplained death or non-syndromic epileptic encephalopathy (PMID: 22457051, 30776697, 32921676). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 192255). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCND3 protein function. Experimental studies have shown that this missense change affects KCND3 function (PMID: 22457051). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 392 of the KCND3 protein (p.Val392Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L;L;L
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Pathogenic	0.84
Sift	Benign	0.090	T;T;T
Sift4G	Benign	0.079	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.83
MutPred		0.51		Loss of catalytic residue at V392 (P = 0.1351);Loss of catalytic residue at V392 (P = 0.1351);Loss of catalytic residue at V392 (P = 0.1351);
MVP		0.94
MPC		1.6
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.31
gMVP		0.92
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205867; hg19: chr1-112329661; COSMIC: COSV105875993;