NM_014363.6(SACS):c.7080_7084del (p.His2362fs) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 9, 2021
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:: RCV001919725.4

Allele description [Variation Report for NM_014363.6(SACS):c.7080_7084del (p.His2362fs)]

NM_014363.6(SACS):c.7080_7084del (p.His2362fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.7080_7084del (p.His2362fs)

HGVS:

NC_000013.11:g.23336796_23336800del
NG_012342.1:g.101907_101911del
NM_001278055.2:c.6639_6643del
NM_014363.6:c.7080_7084delMANE SELECT
NP_001264984.1:p.His2215fs
NP_055178.3:p.His2362fs
NC_000013.10:g.23910931_23910935del
NC_000013.10:g.23910935_23910939del

Protein change:

H2215fs

Links:

dbSNP: rs1294102415

NCBI 1000 Genomes Browser:

rs1294102415

Molecular consequence:

NM_001278055.2:c.6639_6643del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.7080_7084del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Human alpha mannosidase II mRNA, complete cds
gi|1117826|gb|U31520.1|HSU31520

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002165131	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 9, 2021)	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

SCV002165131

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 9, 2021)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002165131.3

#	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.Tyr4538*) 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. This variant has not been reported in the literature in individuals affected with SACS-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His2362Lysfs*3) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2218 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: Sep 29, 2024

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