NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter) AND Spastic paraplegia

Clinical significance:Pathogenic (Last evaluated: Aug 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001386982.1

Allele description [Variation Report for NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter)]

NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter)

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.6434T>A (p.Leu2145Ter)
HGVS:
  • NC_000013.11:g.23337442A>T
  • NG_012342.1:g.101261T>A
  • NM_001278055.2:c.5993T>A
  • NM_014363.6:c.6434T>AMANE SELECT
  • NP_001264984.1:p.Leu1998Ter
  • NP_055178.3:p.Leu2145Ter
  • NC_000013.10:g.23911581A>T
Protein change:
L1998*
Links:
dbSNP: rs770490672
NCBI 1000 Genomes Browser:
rs770490672
Molecular consequence:
  • NM_001278055.2:c.5993T>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_014363.6:c.6434T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Spastic paraplegia
Synonyms:
Spastic paraplegia, lower limb
Identifiers:
MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001587445Invitaecriteria provided, single submitter
Pathogenic
(Aug 20, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.

Guernsey DL, Dubé MP, Jiang H, Asselin G, Blowers S, Evans S, Ferguson M, Macgillivray C, Matsuoka M, Nightingale M, Rideout A, Delatycki M, Orr A, Ludman M, Dooley J, Riddell C, Samuels ME.

J Neurol Sci. 2010 Jan 15;288(1-2):79-87. doi: 10.1016/j.jns.2009.09.034. Epub 2009 Nov 4.

PubMed [citation]
PMID:
19892370

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: compound heterozygotes for nonsense mutations of the SACS gene.

Narayanan V, Rice SG, Olfers SS, Sivakumar K.

J Child Neurol. 2011 Dec;26(12):1585-9. doi: 10.1177/0883073811412825. Epub 2011 Jul 10.

PubMed [citation]
PMID:
21745802
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001587445.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change results in a premature translational stop signal in the SACS gene (p.Leu2145*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2435 amino acids of the SACS protein. This variant is present in population databases (rs770490672, ExAC 0.003%). This variant has not been reported in the literature in individuals with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 689782). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the C-terminus of the SACS protein. Other variant(s) that disrupt this region (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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