rs786205867

chr1-111787039-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 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 where missense usually causes diseases, KCND3
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192255.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr1-111787039-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND3	NM_001378969.1	c.1174G>A	p.Val392Ile	missense_variant	3/8	ENST00000302127.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND3	ENST00000302127.5	c.1174G>A	p.Val392Ile	missense_variant	3/8	5	NM_001378969.1	P3
KCND3	ENST00000315987.6	c.1174G>A	p.Val392Ile	missense_variant	3/8	1		P3
KCND3	ENST00000369697.5	c.1174G>A	p.Val392Ile	missense_variant	2/6	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 9 Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 07, 2022	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2023

Previously reported in a 20-year-old Caucasian male with SUD and a history of two syncopal episodes; however, no premortem ECG was available and familial segregation studies were declined (Giudicessi et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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 (Giudicessi et al., 2012); 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) -

Spinocerebellar ataxia type 19/22 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

ClinVar contains an entry for this variant (Variation ID: 192255). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCND3 function (PMID: 22457051). 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. 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. This variant is not present in population databases (gnomAD no frequency). 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
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	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
MutationTaster	Benign	1.0	D;D;D
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

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

Publications

LitVar

Other links and lift over

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