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

Germline classification:
Pathogenic (5 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:
RCV000853621.16

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:
2

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000899234Taipei Veterans General Hospital, Neurological Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 20, 2019)
germlineclinical testing, in vitro

PubMed (1)
[See all records that cite this PMID]

SCV001430002Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
criteria provided, single submitter

(Classification criteria August 2017)
Pathogenic
(Feb 28, 2020)
germlineclinical testing

Citation Link,

SCV002512703Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 5, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003275863Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 3, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005091240Solve-RD Consortium
no assertion criteria provided
Likely pathogenic
(Jun 1, 2022)
inheritedprovider interpretation

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing, in vitro
not providedgermlineunknown1not providednot provided1yesclinical testing
not providedinheritedyesnot providednot providednot providednot providednot providedprovider interpretation

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providedyesclinical testing PubMed (1)
2not providednot providednot providednot providedin vitro PubMed (1)

Description

SCA19/22-associated mutation

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not provideddiscovery1not providednot providednot provided
2germlineyesnot providednot provideddiscoverynot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1bloodnot provided1not providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003275863.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Solve-RD Consortium, SCV005091240.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

Variant confirmed as disease-causing by referring clinical team

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024