NM_001378969.1(KCND3):c.905G>C (p.Arg302Pro) AND Spinocerebellar ataxia type 19/22

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 21, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002273033.3

Allele description [Variation Report for NM_001378969.1(KCND3):c.905G>C (p.Arg302Pro)]

NM_001378969.1(KCND3):c.905G>C (p.Arg302Pro)

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.905G>C (p.Arg302Pro)

HGVS:

NC_000001.11:g.111981822C>G
NG_032011.2:g.12334G>C
NM_001378969.1:c.905G>CMANE SELECT
NM_001378970.1:c.905G>C
NM_004980.5:c.905G>C
NM_172198.3:c.905G>C
NP_001365898.1:p.Arg302Pro
NP_001365899.1:p.Arg302Pro
NP_004971.2:p.Arg302Pro
NP_751948.1:p.Arg302Pro
LRG_445t1:c.905G>C
LRG_445:g.12334G>C
NC_000001.10:g.112524444C>G
NM_004980.4:c.905G>C

Protein change:

R302P

Links:

dbSNP: rs2101995572

NCBI 1000 Genomes Browser:

rs2101995572

Molecular consequence:

NM_001378969.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378970.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004980.5:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172198.3:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557587	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 21, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17581856, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557587

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 21, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Role of S4 positively charged residues in the regulation of Kv4.3 inactivation and recovery.

Skerritt MR, Campbell DL.

Am J Physiol Cell Physiol. 2007 Sep;293(3):C906-14. Epub 2007 Jun 20.

PubMed [citation]

PMID:: 17581856

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

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557587.2

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

Description

A heterozygous missense variant was identified NM_004980.4(KCND3):c.905G>C in exon 2 of 8 of the KCND3 gene. This substitution is predicted to create a major amino acid change from arginine to proline at position 302 of the protein, NP_004971.2(KCND3):p.(Arg302Pro). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ion transporter functional domain. Functional studies show that changing this residue to an alanine, resulted in reductions in destabilization of the open state and a significant shift to depolarization (Skerritt, M. R. and D. L. Campbell (2007)). In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has not been previously reported in a clinical testing setting. Subsequent analysis of parental samples indicated that this variant is de novo. Based on information available at the time of curation, this variant has been reclassified as LIKELY PATHOGENIC

#	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

Last Updated: Jul 23, 2024

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