NM_014363.6(SACS):c.9678T>G (p.Tyr3226Ter) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 25, 2023
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:: RCV003751950.2

Allele description [Variation Report for NM_014363.6(SACS):c.9678T>G (p.Tyr3226Ter)]

NM_014363.6(SACS):c.9678T>G (p.Tyr3226Ter)

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.9678T>G (p.Tyr3226Ter)

HGVS:

NC_000013.11:g.23334198A>C
NG_012342.1:g.104505T>G
NM_001278055.2:c.9237T>G
NM_014363.6:c.9678T>GMANE SELECT
NP_001264984.1:p.Tyr3079Ter
NP_055178.3:p.Tyr3226Ter
NC_000013.10:g.23908337A>C

Protein change:

Y3079*

Molecular consequence:

NM_001278055.2:c.9237T>G - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.9678T>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004426129	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18465152, 27288452, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004426129

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 25, 2023)

germline

clinical testing

PubMed (3)
[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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004426129.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr3226*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1354 amino acid(s) of the SACS protein. This variant has not been reported in the literature in individuals affected with SACS-related conditions. 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). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

#	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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