NM_014363.6(SACS):c.7250_7254del (p.Thr2417fs) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 3, 2021
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:: RCV001050533.5

Allele description [Variation Report for NM_014363.6(SACS):c.7250_7254del (p.Thr2417fs)]

NM_014363.6(SACS):c.7250_7254del (p.Thr2417fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.7250_7254del (p.Thr2417fs)

HGVS:

NC_000013.11:g.23336624_23336628del
NG_012342.1:g.102077_102081del
NM_001278055.2:c.6809_6813del
NM_014363.6:c.7250_7254delMANE SELECT
NP_001264984.1:p.Thr2270fs
NP_055178.3:p.Thr2417fs
NC_000013.10:g.23910761_23910765del
NC_000013.10:g.23910763_23910767del
NM_014363.5:c.7250_7254del

Protein change:

T2270fs

Links:

dbSNP: rs1868628768

NCBI 1000 Genomes Browser:

rs1868628768

Molecular consequence:

NM_001278055.2:c.6809_6813del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.7250_7254del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Spastic paraplegia
Identifiers:: MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001214648	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 3, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18465152, 27288452, 14718707, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001214648

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 3, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia.

Vermeer S, Meijer RP, Pijl BJ, Timmermans J, Cruysberg JR, Bos MM, Schelhaas HJ, van de Warrenburg BP, Knoers NV, Scheffer H, Kremer B.

Neurogenetics. 2008 Jul;9(3):207-14. doi: 10.1007/s10048-008-0131-7. Epub 2008 May 9. Erratum in: Neurogenetics. 2009 Feb;10(1):87.

PubMed [citation]

PMID:: 18465152
PMCID:: PMC2441586

A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay.

Bradshaw TY, Romano LE, Duncan EJ, Nethisinghe S, Abeti R, Michael GJ, Giunti P, Vermeer S, Chapple JP.

Hum Mol Genet. 2016 Aug 1;25(15):3232-3244. doi: 10.1093/hmg/ddw173. Epub 2016 Jun 10.

PubMed [citation]

PMID:: 27288452
PMCID:: PMC5179924

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001214648.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SACS protein in which other variant(s) (p.Gln4054*) have been determined to be pathogenic (PMID: 18465152, 27288452; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 847067). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 14718707). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr2417Argfs*12) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2163 amino acid(s) of the SACS protein.

#	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: Sep 29, 2024

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