NM_014363.6(SACS):c.1276_1277dup (p.Leu426fs) AND Charlevoix-Saguenay spastic ataxia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 4, 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:: RCV000409220.3

Allele description [Variation Report for NM_014363.6(SACS):c.1276_1277dup (p.Leu426fs)]

NM_014363.6(SACS):c.1276_1277dup (p.Leu426fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.1276_1277dup (p.Leu426fs)

HGVS:

NC_000013.11:g.23355336_23355337dup
NG_012342.1:g.83367_83368dup
NM_001278055.2:c.835_836dup
NM_014363.6:c.1276_1277dupMANE SELECT
NP_001264984.1:p.Leu279fs
NP_055178.3:p.Leu426fs
NC_000013.10:g.23929475_23929476dup
NM_014363.4:c.1276_1277dupTT
NM_014363.5:c.1276_1277dupTT

Protein change:

L279fs

Links:

dbSNP: rs1057516406

NCBI 1000 Genomes Browser:

rs1057516406

Molecular consequence:

NM_001278055.2:c.835_836dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.1276_1277dup - 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
SCV000485614	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 13, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV002500102	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 4, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000485614

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Jan 13, 2016)

unknown

clinical testing

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV002500102

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 4, 2022)

germline

clinical testing

Citation Link

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

Details of each submission

From Counsyl, SCV000485614.2

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

#	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, SCV002500102.1

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

Description

Variant summary: SACS c.1276_1277dupTT (p.Leu426PhefsX53) 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 251414 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1276_1277dupTT in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. 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

Last Updated: Dec 24, 2022

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