NM_014363.6(SACS):c.8799T>A (p.Tyr2933Ter) AND Spastic paraplegia

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 8, 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:: RCV003752193.1

Allele description

NM_014363.6(SACS):c.8799T>A (p.Tyr2933Ter)

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.8799T>A (p.Tyr2933Ter)

HGVS:

NC_000013.11:g.23335077A>T
NG_012342.1:g.103626T>A
NM_001278055.2:c.8358T>A
NM_014363.6:c.8799T>AMANE SELECT
NP_001264984.1:p.Tyr2786Ter
NP_055178.3:p.Tyr2933Ter
NC_000013.10:g.23909216A>T

Protein change:

Y2786*

Molecular consequence:

NM_001278055.2:c.8358T>A - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.8799T>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
SCV004502803	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23785480, 26288984, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004502803

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 8, 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

Novel SACS mutations identified by whole exome sequencing in a norwegian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Tzoulis C, Johansson S, Haukanes BI, Boman H, Knappskog PM, Bindoff LA.

PLoS One. 2013 Jun 13;8(6):e66145. doi: 10.1371/journal.pone.0066145. Print 2013.

PubMed [citation]

PMID:: 23785480
PMCID:: PMC3681964

New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Pilliod J, Moutton S, Lavie J, Maurat E, Hubert C, Bellance N, Anheim M, Forlani S, Mochel F, N'Guyen K, Thauvin-Robinet C, Verny C, Milea D, Lesca G, Koenig M, Rodriguez D, Houcinat N, Van-Gils J, Durand CM, Guichet A, Barth M, Bonneau D, et al.

Ann Neurol. 2015 Dec;78(6):871-86. doi: 10.1002/ana.24509. Epub 2015 Nov 14.

PubMed [citation]

PMID:: 26288984

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004502803.1

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

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.Leu4451Pro) have been determined to be pathogenic (PMID: 23785480, 26288984). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SACS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr2933*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1647 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: Feb 28, 2024

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