NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter) AND Spastic paraplegia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 11, 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:: RCV001386982.7

Allele description [Variation Report for NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter)]

NM_014363.6(SACS):c.6434T>A (p.Leu2145Ter)

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.6434T>A (p.Leu2145Ter)

HGVS:

NC_000013.11:g.23337442A>T
NG_012342.1:g.101261T>A
NM_001278055.2:c.5993T>A
NM_014363.6:c.6434T>AMANE SELECT
NP_001264984.1:p.Leu1998Ter
NP_055178.3:p.Leu2145Ter
NC_000013.10:g.23911581A>T

Protein change:

L1998*

Links:

dbSNP: rs770490672

NCBI 1000 Genomes Browser:

rs770490672

Molecular consequence:

NM_001278055.2:c.5993T>A - nonsense - [Sequence Ontology: SO:0001587]
NM_014363.6:c.6434T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

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Retrograde Ejaculation
Retrograde Ejaculation
The flow of SEMINAL FLUID, from the posterior URETHRA, backwards into the BLADDER. Causes include injuries such as from SPINAL CORD INJURIES; DIABETIC NEUROPATHIES; surgeries ...<br/>Year introduced: 2024

MeSH
Ejaculatory Dysfunction
Ejaculatory Dysfunction
The inability in males to ejaculate, or to have a normal time to EJACULATION.<br/>Year introduced: 2024

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001587445	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19892370, 21745802, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001587445

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 11, 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 mutations in the sacsin gene in ataxia patients from Maritime Canada.

Guernsey DL, Dubé MP, Jiang H, Asselin G, Blowers S, Evans S, Ferguson M, Macgillivray C, Matsuoka M, Nightingale M, Rideout A, Delatycki M, Orr A, Ludman M, Dooley J, Riddell C, Samuels ME.

J Neurol Sci. 2010 Jan 15;288(1-2):79-87. doi: 10.1016/j.jns.2009.09.034. Epub 2009 Nov 4.

PubMed [citation]

PMID:: 19892370

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: compound heterozygotes for nonsense mutations of the SACS gene.

Narayanan V, Rice SG, Olfers SS, Sivakumar K.

J Child Neurol. 2011 Dec;26(12):1585-9. doi: 10.1177/0883073811412825. Epub 2011 Jul 10.

PubMed [citation]

PMID:: 21745802

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587445.4

#	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.Leu2145*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2435 amino acid(s) of the SACS protein. This variant is present in population databases (rs770490672, gnomAD 0.0009%). 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: 689782). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). 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: Sep 29, 2024

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