NM_014363.6(SACS):c.10466_10467del (p.Ser3489fs) AND Charlevoix-Saguenay spastic ataxia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 16, 2023
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:: RCV000168999.4

Allele description [Variation Report for NM_014363.6(SACS):c.10466_10467del (p.Ser3489fs)]

NM_014363.6(SACS):c.10466_10467del (p.Ser3489fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.10466_10467del (p.Ser3489fs)

HGVS:

NC_000013.11:g.23333410GA[2]
NG_012342.1:g.105289CT[2]
NM_001278055.2:c.10025_10026del
NM_014363.6:c.10466_10467delMANE SELECT
NP_001264984.1:p.Ser3342fs
NP_055178.3:p.Ser3489fs
NC_000013.10:g.23907548_23907549del
NC_000013.10:g.23907549GA[2]
NM_014363.4:c.10466_10467delCT
NM_014363.5:c.10466_10467delCT

Protein change:

S3342fs

Links:

dbSNP: rs786204416

NCBI 1000 Genomes Browser:

rs786204416

Molecular consequence:

NM_001278055.2:c.10025_10026del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.10466_10467del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000220137	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 6, 2014)	unknown	literature only	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001983640	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 18, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26530509, 21597885 Citation Link,
SCV004209932	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220137

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Mar 6, 2014)

unknown

literature only

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

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV001983640

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Sep 18, 2021)

germline

clinical testing

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

Citation Link,

SCV004209932

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Criscuolo C, Procaccini C, Meschini MC, Cianflone A, Carbone R, Doccini S, Devos D, Nesti C, Vuillaume I, Pellegrino M, Filla A, De Michele G, Matarese G, Santorelli FM.

J Neurol. 2015 Dec;262(12):2755-63. doi: 10.1007/s00415-015-7911-4. Epub 2015 Nov 3.

PubMed [citation]

PMID:: 26530509

Thickening of peripapillar retinal fibers for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Desserre J, Devos D, Sautière BG, Debruyne P, Santorelli FM, Vuillaume I, Defoort-Dhellemmes S.

Cerebellum. 2011 Dec;10(4):758-62. doi: 10.1007/s12311-011-0286-x.

PubMed [citation]

PMID:: 21597885

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000220137.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	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, SCV001983640.1

#	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.10466_10467delCT (p.Ser3489LeufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245712 control chromosomes. c.10466_10467delCT has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and has been subsequently cited by others (example Desserre_2011, Criscuolo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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

From Baylor Genetics, SCV004209932.1

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

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

Last Updated: Sep 29, 2024

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