NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln) AND Spinocerebellar ataxia type 6

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 23, 2023
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:: RCV000059302.10

Allele description [Variation Report for NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)]

NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)

Gene:

CACNA1A:calcium voltage-gated channel subunit alpha1 A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)

HGVS:

NC_000019.10:g.13235693C>T
NG_011569.1:g.275768G>A
NM_000068.4:c.5006G>A
NM_001127221.2:c.4991G>A
NM_001127222.2:c.4988G>AMANE SELECT
NM_001174080.2:c.4997G>A
NM_023035.3:c.5006G>A
NP_000059.3:p.Arg1669Gln
NP_001120693.1:p.Arg1664Gln
NP_001120693.1:p.Arg1664Gln
NP_001120694.1:p.Arg1663Gln
NP_001167551.1:p.Arg1666Gln
NP_075461.2:p.Arg1669Gln
LRG_7t1:c.4991G>A
LRG_7:g.275768G>A
LRG_7p1:p.Arg1664Gln
NC_000019.9:g.13346507C>T
NM_000068.2:c.4991G>A
NM_001127221.1:c.4991G>A
NM_001127221.2:c.4991G>A
NM_023035.2:c.5006G>A

Protein change:

R1663Q

Links:

UniProtKB/Swiss-Prot: VAR_063691; dbSNP: rs121908247

NCBI 1000 Genomes Browser:

rs121908247

Molecular consequence:

NM_000068.4:c.5006G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127221.2:c.4991G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127222.2:c.4988G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001174080.2:c.4997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_023035.3:c.5006G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Spinocerebellar ataxia type 6 (SCA6)
Identifiers:: MONDO: MONDO:0008457; MedGen: C0752124; Orphanet: 98758; OMIM: 183086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000090860	UniProtKB/Swiss-Prot	no classification provided	not provided	unknown	not provided
SCV003841799	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16325861, 28742085, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000090860

UniProtKB/Swiss-Prot

no classification provided

not provided

unknown

not provided

SCV003841799

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene.

Tonelli A, D'Angelo MG, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi AC, Bresolin N, Bassi MT.

J Neurol Sci. 2006 Feb 15;241(1-2):13-7. Epub 2005 Dec 2.

PubMed [citation]

PMID:: 16325861

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

Luo X, Rosenfeld JA, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga KJ, Pastore MT, Bartholomew D, Delgado MR, Rotenberg J, Lewis RA, Emrick L, Bacino CA, Eldomery MK, Coban Akdemir Z, Xia F, Yang Y, Lalani SR, Lotze T, Lupski JR, Lee B, et al.

PLoS Genet. 2017 Jul;13(7):e1006905. doi: 10.1371/journal.pgen.1006905.

PubMed [citation]

PMID:: 28742085
PMCID:: PMC5557584

See all PubMed Citations (3)

Details of each submission

From UniProtKB/Swiss-Prot, SCV000090860.1

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

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

From 3billion, SCV003841799.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068432). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 28742085). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16325861, 28742085). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Nov 10, 2024

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