NM_014363.6(SACS):c.8793del (p.Lys2931fs) AND Charlevoix-Saguenay spastic ataxia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 11, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000674417.4

Allele description [Variation Report for NM_014363.6(SACS):c.8793del (p.Lys2931fs)]

NM_014363.6(SACS):c.8793del (p.Lys2931fs)

Gene:
SACS:sacsin molecular chaperone [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q12.12
Genomic location:
Preferred name:
NM_014363.6(SACS):c.8793del (p.Lys2931fs)
HGVS:
  • NC_000013.11:g.23335089del
  • NG_012342.1:g.103620del
  • NM_001278055.2:c.8352del
  • NM_014363.6:c.8793delMANE SELECT
  • NP_001264984.1:p.Lys2784fs
  • NP_055178.3:p.Lys2931fs
  • NC_000013.10:g.23909222del
  • NC_000013.10:g.23909228del
  • NM_014363.4:c.8793del
  • NM_014363.4:c.8793delA
  • NM_014363.5:c.8793del
  • NM_014363.5:c.8793delA
Protein change:
K2784fs
Links:
dbSNP: rs767871841
NCBI 1000 Genomes Browser:
rs767871841
Molecular consequence:
  • NM_001278055.2:c.8352del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_014363.6:c.8793del - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Charlevoix-Saguenay spastic ataxia (SACS)
Synonyms:
Autosomal recessive spastic ataxia of Charlevoix-Saguenay; Spastic ataxia of Charlevoix-Saguenay; SPASTIC ATAXIA 6, AUTOSOMAL RECESSIVE
Identifiers:
MONDO: MONDO:0010041; MedGen: C1849140; Orphanet: 98; OMIM: 270550

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000799750Counsylcriteria provided, single submitter
Likely pathogenic
(May 4, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001149910Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Pathogenic
(Apr 6, 2018)
germlineclinical testing

Citation Link,

SCV001737737Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 11, 2021)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot provided1not providedclinical testing

Citations

PubMed

Novel compound heterozygous mutations in sacsin-related ataxia.

Yamamoto Y, Hiraoka K, Araki M, Nagano S, Shimazaki H, Takiyama Y, Sakoda S.

J Neurol Sci. 2005 Dec 15;239(1):101-4. Epub 2005 Sep 29.

PubMed [citation]
PMID:
16198375

Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.

Shakya S, Kumari R, Suroliya V, Tyagi N, Joshi A, Garg A, Singh I, Kalikavil Puthanveedu D, Cherian A, Mukerji M, Srivastava AK, Faruq M.

Clin Genet. 2019 Dec;96(6):566-574. doi: 10.1111/cge.13625. Epub 2019 Sep 1.

PubMed [citation]
PMID:
31429931
See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000799750.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, Klinikum rechts der Isar, SCV001149910.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1bloodnot provided1not providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001737737.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: SACS c.8793delA (p.Lys2931AsnfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250652 control chromosomes. c.8793delA has been reported in the literature as a homozygous mutation in several individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay, including 2 affected siblings (e.g. Hara_2005, Shakya_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 16, 2021

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