NM_014363.6(SACS):c.5405_5408del (p.Lys1802fs) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 18, 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:: RCV003750973.2

Allele description [Variation Report for NM_014363.6(SACS):c.5405_5408del (p.Lys1802fs)]

NM_014363.6(SACS):c.5405_5408del (p.Lys1802fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.5405_5408del (p.Lys1802fs)

HGVS:

NC_000013.11:g.23338470_23338473del
NG_012342.1:g.100232_100235del
NM_001278055.2:c.4964_4967del
NM_014363.6:c.5405_5408delMANE SELECT
NP_001264984.1:p.Lys1655fs
NP_055178.3:p.Lys1802fs
NC_000013.10:g.23912607_23912610del
NC_000013.10:g.23912609_23912612del

Protein change:

K1655fs

Molecular consequence:

NM_001278055.2:c.4964_4967del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.5405_5408del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

Recent activity

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Homo sapiens KIAA0746 protein (KIAA0746), mRNA
Homo sapiens KIAA0746 protein (KIAA0746), mRNA
gi|142379857|ref|NM_015187.2|

Nucleotide
Collybia sordida
Collybia sordida
Genome sequence analysis of a fairy ring-forming fungus Lepista sordida

BioProject
JGI_CAAO4999.rev NIH_XGC_tropTe5 Xenopus tropicalis cDNA clone CAAO4999 3', mRNA...
JGI_CAAO4999.rev NIH_XGC_tropTe5 Xenopus tropicalis cDNA clone CAAO4999 3', mRNA sequence
gi|71938089|gnl|dbEST|30599323|gb|C 84.2|

Nucleotide
JGI_CAAO5016.fwd NIH_XGC_tropTe5 Xenopus tropicalis cDNA clone CAAO5016 5', mRNA...
JGI_CAAO5016.fwd NIH_XGC_tropTe5 Xenopus tropicalis cDNA clone CAAO5016 5', mRNA sequence
gi|58726375|gnl|dbEST|27643536|gb|C 17.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004524190	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 18, 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

SCV004524190

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 18, 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, SCV004524190.1

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

Description

This sequence change creates a premature translational stop signal (p.Lys1802Serfs*11) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2778 amino acid(s) of the SACS protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SACS-related conditions. 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. For these reasons, this variant has been classified as 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: Sep 29, 2024

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