NM_014363.6(SACS):c.9404T>C (p.Leu3135Ser) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 27, 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:: RCV000463355.8

Allele description [Variation Report for NM_014363.6(SACS):c.9404T>C (p.Leu3135Ser)]

NM_014363.6(SACS):c.9404T>C (p.Leu3135Ser)

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.9404T>C (p.Leu3135Ser)

HGVS:

NC_000013.11:g.23334472A>G
NG_012342.1:g.104231T>C
NM_001278055.2:c.8963T>C
NM_014363.6:c.9404T>CMANE SELECT
NP_001264984.1:p.Leu2988Ser
NP_055178.3:p.Leu3135Ser
NC_000013.10:g.23908611A>G
NM_014363.4:c.9404T>C
NM_014363.5:c.9404T>C

Protein change:

L2988S

Links:

dbSNP: rs371019314

NCBI 1000 Genomes Browser:

rs371019314

Molecular consequence:

NM_001278055.2:c.8963T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014363.6:c.9404T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000552965	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 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

SCV000552965

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 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, SCV000552965.9

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3135 of the SACS protein (p.Leu3135Ser). This variant is present in population databases (rs371019314, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 29538656; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SACS protein function with a negative predictive value of 95%. 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: Jun 29, 2024

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