NM_014363.6(SACS):c.5296G>T (p.Glu1766Ter) AND Charlevoix-Saguenay spastic ataxia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 26, 2024
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:: RCV002281768.3

Allele description [Variation Report for NM_014363.6(SACS):c.5296G>T (p.Glu1766Ter)]

NM_014363.6(SACS):c.5296G>T (p.Glu1766Ter)

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.5296G>T (p.Glu1766Ter)

HGVS:

NC_000013.11:g.23338580C>A
NG_012342.1:g.100123G>T
NM_001278055.2:c.4855G>T
NM_014363.6:c.5296G>TMANE SELECT
NP_001264984.1:p.Glu1619Ter
NP_055178.3:p.Glu1766Ter
NC_000013.10:g.23912719C>A
NM_014363.5:c.5296G>T

Protein change:

E1619*

Molecular consequence:

NM_001278055.2:c.4855G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.5296G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002572143	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 18, 2022)	germline	clinical testing	Citation Link,
SCV004806654	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	germline	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

SCV002572143

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 18, 2022)

germline

clinical testing

Citation Link,

SCV004806654

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 26, 2024)

germline

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

Citations

PubMed

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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572143.1

#	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.5296G>T (p.Glu1766X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not predicted to cause nonsense mediated decay, truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251108 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5296G>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have 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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806654.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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