13-23335082-GTTTT-GTTTTT

Variant names:

• chr13-23335082-G-GT
• rs767871841
• NM_014363.6:c.8793dupA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014363.6(SACS):​c.8793dupA​(p.Arg2932ThrfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SACS NM_014363.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.798
• Publications: 4 publications found

Genes affected

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 324 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-23335082-G-GT is Pathogenic according to our data. Variant chr13-23335082-G-GT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 959991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6	c.8793dupA	p.Arg2932ThrfsTer7	frameshift_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.8793dupA	p.Arg2932ThrfsTer7	frameshift_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250652 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461286 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4 AN XY: 726894

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111620

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74272

African (AFR) AF: 0.0000483 AC: 2 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 1648 amino acids are replaced with 6 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11788093, 34663476, 10655055, 19892370, 22307627, 21745802) -

Sep 08, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the SACS gene demonstrated a one base pair duplication in exon 10, c.8793dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 7 amino acids downstream of the variant, p.Arg2932Thrfs*7. This sequence change is not predicted to result in nonsense mediated decay, but does disrupt the c-terminal domain of the SACS protein. This sequencing change has been described in the gnomAD database with a low overall population frequency of 0.001% and a frequency of 0.004% in the African sub group (dbSNP rs767871841). Other truncating variants within this region and downstream of this variant have been reported in patients with SACS-related disorders (PMIDs: 18465152, 15156359, 22816526). Collectively these evidences indicate that, this p.Arg2932Thrfs*7 sequence change is pathogenic. -

Jun 10, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

Charlevoix-Saguenay spastic ataxia Pathogenic:3

Mar 20, 2024

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Pathogenic:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg2932Thrfs*7) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1648 amino acid(s) of the SACS protein. This variant is present in population databases (rs767871841, gnomAD 0.004%). 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: 959991). This variant disrupts a region of the SACS protein in which other variant(s) (p.Ile2949Phefs*4, p.Arg3903*) have been determined to be pathogenic (PMID: 10655055, 11788093, 19892370, 21745802, 22307627). 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. -

Hereditary spastic paraplegia Pathogenic:1

Feb 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767871841; hg19: chr13-23909221; COSMIC: COSV66544123;