NM_014363.6(SACS):c.5836T>C (p.Trp1946Arg) AND Charlevoix-Saguenay spastic ataxia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 12, 2022
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:: RCV000005852.4

Allele description [Variation Report for NM_014363.6(SACS):c.5836T>C (p.Trp1946Arg)]

NM_014363.6(SACS):c.5836T>C (p.Trp1946Arg)

Gene:

SACS:sacsin molecular chaperone [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.5836T>C (p.Trp1946Arg)

Other names:

W1196R

HGVS:

NC_000013.11:g.23338040A>G
NG_012342.1:g.100663T>C
NM_001278055.2:c.5395T>C
NM_014363.6:c.5836T>CMANE SELECT
NP_001264984.1:p.Trp1799Arg
NP_055178.3:p.Trp1946Arg
NC_000013.10:g.23912179A>G
NM_014363.5:c.5836T>C
Q9NZJ4:p.Trp1946Arg

Protein change:

W1799R; TRP1196ARG

Links:

UniProtKB: Q9NZJ4#VAR_064811; OMIM: 604490.0006; dbSNP: rs137853017

NCBI 1000 Genomes Browser:

rs137853017

Molecular consequence:

NM_001278055.2:c.5395T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014363.6:c.5836T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charlevoix-Saguenay spastic ataxia (SACS)
Synonyms:: Autosomal recessive spastic ataxia of Charlevoix-Saguenay; Spastic ataxia of Charlevoix-Saguenay; SPASTIC ATAXIA 6, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0010041; MedGen: C1849140; Orphanet: 98; OMIM: 270550

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026034	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2003)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002766372	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23250129, 12873855 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000026034

OMIM

no assertion criteria provided

Pathogenic
(Jul 1, 2003)

germline

literature only

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

SCV002766372

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 12, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Diversity of ARSACS mutations in French-Canadians.

Thiffault I, Dicaire MJ, Tetreault M, Huang KN, Demers-Lamarche J, Bernard G, Duquette A, Larivière R, Gehring K, Montpetit A, McPherson PS, Richter A, Montermini L, Mercier J, Mitchell GA, Dupré N, Prévost C, Bouchard JP, Mathieu J, Brais B.

Can J Neurol Sci. 2013 Jan;40(1):61-6.

PubMed [citation]

PMID:: 23250129

Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia.

El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY, Belal S, Siddique T, Hentati F.

Arch Neurol. 2003 Jul;60(7):982-8.

PubMed [citation]

PMID:: 12873855

Details of each submission

From OMIM, SCV000026034.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Tunisian family with autosomal recessive ataxia similar to spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), El Euch-Fayache et al. (2003) identified a 3662T-C transition in the SACS gene, resulting in a trp1196-to-arg (W1196R) substitution. The mutation was not identified in 100 control chromosomes.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766372.1

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

Description

Variant summary: SACS c.5836T>C (p.Trp1946Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250862 control chromosomes (gnomAD). c.5836T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g. El Euch-Fayache_2003, Thiffault_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Nov 10, 2024

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