NM_014363.6(SACS):c.7273C>T (p.Arg2425Ter) AND Charlevoix-Saguenay spastic ataxia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 16, 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:: RCV000412060.5

Allele description [Variation Report for NM_014363.6(SACS):c.7273C>T (p.Arg2425Ter)]

NM_014363.6(SACS):c.7273C>T (p.Arg2425Ter)

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.7273C>T (p.Arg2425Ter)

HGVS:

NC_000013.11:g.23336603G>A
NG_012342.1:g.102100C>T
NM_001278055.2:c.6832C>T
NM_014363.6:c.7273C>TMANE SELECT
NP_001264984.1:p.Arg2278Ter
NP_055178.3:p.Arg2425Ter
NC_000013.10:g.23910742G>A
NM_014363.4:c.7273C>T
NM_014363.5:c.7273C>T

Protein change:

R2278*

Links:

dbSNP: rs145766983

NCBI 1000 Genomes Browser:

rs145766983

Molecular consequence:

NM_001278055.2:c.6832C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.7273C>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

Recent activity

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Mus musculus CD4 antigen (Cd4), mRNA
Mus musculus CD4 antigen (Cd4), mRNA
gi|1344169072|ref|NM_013488.3|

Nucleotide
IZUMO1R [Mustela nigripes]
IZUMO1R [Mustela nigripes]
Gene ID:132025480

Gene
PIG-M [Ctenocephalides felis]
PIG-M [Ctenocephalides felis]
Gene ID:113389057

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485731	Counsyl	no assertion criteria provided	Likely pathogenic (Feb 4, 2016)	unknown	clinical testing
SCV002027642	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766371	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 16, 2022)	germline	clinical testing	Citation Link,
SCV004202293	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 20, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

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 Counsyl, SCV000485731.2

#	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 Genome-Nilou Lab, SCV002027642.1

#	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	no	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, SCV002766371.1

#	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.7273C>T (p.Arg2425X) results in a premature termination codon, which are commonly known mechanisms for disease. While the variant is not predicted to lead to nonsense-mediated decay, it does disrupt the last 2155 amino acids of the protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249774 control chromosomes. To our knowledge, no occurrence of c.7273C>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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/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

From Baylor Genetics, SCV004202293.1

#	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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