NM_014363.6(SACS):c.13614C>A (p.Tyr4538Ter) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 7, 2024
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:: RCV001045016.5

Allele description [Variation Report for NM_014363.6(SACS):c.13614C>A (p.Tyr4538Ter)]

NM_014363.6(SACS):c.13614C>A (p.Tyr4538Ter)

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.13614C>A (p.Tyr4538Ter)

HGVS:

NC_000013.11:g.23330262G>T
NG_012342.1:g.108441C>A
NM_001278055.2:c.13173C>A
NM_014363.6:c.13614C>AMANE SELECT
NP_001264984.1:p.Tyr4391Ter
NP_055178.3:p.Tyr4538Ter
NC_000013.10:g.23904401G>T
NM_014363.5:c.13614C>A

Protein change:

Y4391*

Links:

dbSNP: rs927804920

NCBI 1000 Genomes Browser:

rs927804920

Molecular consequence:

NM_001278055.2:c.13173C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.13614C>A - 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
SCV001208843	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15156359, 21507954, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001208843

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 7, 2024)

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

Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey.

Richter AM, Ozgul RK, Poisson VC, Topaloglu H.

Neurogenetics. 2004 Sep;5(3):165-70. Epub 2004 May 20.

PubMed [citation]

PMID:: 15156359

Structural basis of defects in the sacsin HEPN domain responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

Kozlov G, Denisov AY, Girard M, Dicaire MJ, Hamlin J, McPherson PS, Brais B, Gehring K.

J Biol Chem. 2011 Jun 10;286(23):20407-12. doi: 10.1074/jbc.M111.232884. Epub 2011 Apr 20.

PubMed [citation]

PMID:: 21507954
PMCID:: PMC3121481

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001208843.5

#	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.Tyr4538*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 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. ClinVar contains an entry for this variant (Variation ID: 842578). This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). 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: Feb 28, 2024

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