NM_014363.6(SACS):c.9956_9957del (p.Lys3319fs) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 28, 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:: RCV001862751.3

Allele description [Variation Report for NM_014363.6(SACS):c.9956_9957del (p.Lys3319fs)]

NM_014363.6(SACS):c.9956_9957del (p.Lys3319fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.9956_9957del (p.Lys3319fs)

HGVS:

NC_000013.11:g.23333920_23333921del
NG_012342.1:g.104783_104784del
NM_001278055.2:c.9515_9516del
NM_014363.6:c.9956_9957delMANE SELECT
NP_001264984.1:p.Lys3172fs
NP_055178.3:p.Lys3319fs
NC_000013.10:g.23908058_23908059del
NC_000013.10:g.23908059_23908060del
NM_014363.4:c.9956_9957delAA

Protein change:

K3172fs

Links:

dbSNP: rs772704931

NCBI 1000 Genomes Browser:

rs772704931

Molecular consequence:

NM_001278055.2:c.9515_9516del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.9956_9957del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002232725	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29538656, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002232725

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 28, 2023)

germline

clinical testing

PubMed (2)
[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

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Parkinson MH, Bartmann AP, Clayton LMS, Nethisinghe S, Pfundt R, Chapple JP, Reilly MM, Manji H, Wood NJ, Bremner F, Giunti P.

Brain. 2018 Apr 1;141(4):989-999. doi: 10.1093/brain/awy028.

PubMed [citation]

PMID:: 29538656

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002232725.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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 (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 817415). This premature translational stop signal has been observed in individual(s) with spastic ataxia (PMID: 29538656). This variant is present in population databases (rs772704931, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Lys3319Serfs*56) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1261 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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