rs1057521793

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_001378969.1(KCND3):c.1111G>A(p.Gly371Arg) 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. 13/21 in silico tools predict a damaging 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

LOC124904312 (HGNC:):

LOC124904312 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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, 4 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, Brugada syndrome 1, Brugada syndrome 9.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 1-111787102-C-T is Pathogenic according to our data. Variant chr1-111787102-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383943.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1 link	c.1111G>A	p.Gly371Arg	missense_variant	Exon 3 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCND3	ENST00000302127.5 link	c.1111G>A	p.Gly371Arg	missense_variant	Exon 3 of 8	5	NM_001378969.1	ENSP00000306923.4	Q9UK17-1
KCND3	ENST00000315987.6 link	c.1111G>A	p.Gly371Arg	missense_variant	Exon 3 of 8	1		ENSP00000319591.2	Q9UK17-1
KCND3	ENST00000369697.5 link	c.1111G>A	p.Gly371Arg	missense_variant	Exon 2 of 6	1		ENSP00000358711.1	Q9UK17-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 19/22

Pathogenic:2Uncertain:1

Sep 21, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 371 of the KCND3 protein (p.Gly371Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autism, developmental disorders and/or clinical features of spinocerebellar ataxia (PMID: 31017293, 33057194, 35982159). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 383943). Invitae Evidence 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 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. 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. -

Nov 06, 2018

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Dec 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31017293) -

Apr 23, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Neurodevelopmental delay

Pathogenic:1

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Brugada syndrome 9

Pathogenic:1

Jun 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1111G>A;p.(Gly371Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 383943; PMID: 31017293) - PS4_supporting. This variant is not present in population databases:rs1057521793, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 31017293 ) PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

H;H;H

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.91

MutPred

0.92

Gain of glycosylation at T367 (P = 0.1263);Gain of glycosylation at T367 (P = 0.1263);Gain of glycosylation at T367 (P = 0.1263);

MVP

1.0

MPC

2.9

ClinPred

1.0

GERP RS

4.8

Varity_R

0.90

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over