NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met) AND Spinocerebellar ataxia type 19/22

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000853621.14

Allele description [Variation Report for NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)]

NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)

Gene:

KCND3:potassium voltage-gated channel subfamily D member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.2

Genomic location:

Preferred name:

NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)

HGVS:

NC_000001.11:g.111787083G>A
NG_032011.2:g.207073C>T
NM_001378969.1:c.1130C>TMANE SELECT
NM_001378970.1:c.1130C>T
NM_004980.5:c.1130C>T
NM_172198.3:c.1130C>T
NP_001365898.1:p.Thr377Met
NP_001365899.1:p.Thr377Met
NP_004971.2:p.Thr377Met
NP_004971.2:p.Thr377Met
NP_751948.1:p.Thr377Met
LRG_445t1:c.1130C>T
LRG_445:g.207073C>T
LRG_445p1:p.Thr377Met
NC_000001.10:g.112329705G>A
NM_001378969.1:c.1130C>T
NM_004980.4:c.1130C>T

Protein change:

T377M

Links:

dbSNP: rs1571636501

NCBI 1000 Genomes Browser:

rs1571636501

Molecular consequence:

NM_001378969.1:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378970.1:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004980.5:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172198.3:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Spinocerebellar ataxia type 19/22 (SCA19)
Synonyms:: Spinocerebellar ataxia 19; Spinocerebellar ataxia 22
Identifiers:: MONDO: MONDO:0011819; MedGen: C1846367; Orphanet: 98772; OMIM: 607346

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copper ion binding / methyltransferase [Arabidopsis thaliana]
copper ion binding / methyltransferase [Arabidopsis thaliana]
Gene ID:842768

Gene
At.66862 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000899234	Taipei Veterans General Hospital, Neurological Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2019)	germline	clinical testing, in vitro	PubMed (1) [See all records that cite this PMID]
SCV001430002	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Feb 28, 2020)	germline	clinical testing	Citation Link,
SCV002512703	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003275863	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23280837, 29527639, 31293010, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	yes	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing, in vitro

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mutations in KCND3 cause spinocerebellar ataxia type 22.

Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW.

Ann Neurol. 2012 Dec;72(6):859-69. doi: 10.1002/ana.23701.

PubMed [citation]

PMID:: 23280837
PMCID:: PMC4085146

See all PubMed Citations (5)

Details of each submission

From Taipei Veterans General Hospital, Neurological Institute, SCV000899234.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	clinical testing	PubMed (1)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

Description

SCA19/22-associated mutation

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	discovery		1	not provided	not provided	not provided
2	germline	yes	not provided	not provided	discovery		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001430002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512703.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PP1 strong, PP2 supporting, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003275863.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense change has been observed in individuals with spinocerebellar ataxia (PMID: 23280837, 29527639). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCND3 function (PMID: 31293010). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 626319). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 377 of the KCND3 protein (p.Thr377Met).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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