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NM_014363.6(SACS):c.12673_12677del (p.Tyr4225fs) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 28, 2022
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:
RCV002571457.2

Allele description [Variation Report for NM_014363.6(SACS):c.12673_12677del (p.Tyr4225fs)]

NM_014363.6(SACS):c.12673_12677del (p.Tyr4225fs)

Gene:
SACS:sacsin molecular chaperone [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q12.12
Genomic location:
Preferred name:
NM_014363.6(SACS):c.12673_12677del (p.Tyr4225fs)
HGVS:
  • NC_000013.11:g.23331200_23331204del
  • NG_012342.1:g.107500_107504del
  • NM_001278055.2:c.12232_12236del
  • NM_014363.4:c.12673_12677delTATCA
  • NM_014363.6:c.12673_12677delMANE SELECT
  • NP_001264984.1:p.Tyr4078fs
  • NP_055178.3:p.Tyr4225fs
  • NC_000013.10:g.23905338_23905342del
  • NC_000013.10:g.23905339_23905343del
  • NM_014363.5:c.12673_12677delTATCA
Protein change:
Y4078fs
Molecular consequence:
  • NM_001278055.2:c.12232_12236del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_014363.6:c.12673_12677del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003627491Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 28, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Autosomal recessive spastic ataxia of Charlevoix-Saguenay caused by novel mutations in SACS gene: A report of two Chinese families.

Wang Z, Song Y, Wang X, Li X, Xu F, Si L, Dong Y, Yao T, Zhu J, Lai H, Li W, Lin F, Huang H, Wang C.

Neurosci Lett. 2021 May 1;752:135831. doi: 10.1016/j.neulet.2021.135831. Epub 2021 Mar 18.

PubMed [citation]
PMID:
33746006

Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations.

Chen J, Zhao Z, Shen H, Bing Q, Li N, Guo X, Hu J.

BMC Neurol. 2022 May 16;22(1):180. doi: 10.1186/s12883-022-02708-z.

PubMed [citation]
PMID:
35578252
PMCID:
PMC9109329

Details of each submission

From Ambry Genetics, SCV003627491.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The c.12673_12677delTATCA (p.Y4225Dfs*6) alteration, located in exon 10 (coding exon 9) of the SACS gene, consists of a deletion of 5 nucleotides from position 12673 to 12677, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration occurs at the 3' terminus of the SACS gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 8% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of <0.01% (2/250648) total alleles studied. The highest observed frequency was <0.01% (2/113238) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in conjunction with another disease-causing SACS alteration, in multiple unrelated individuals with spastic ataxia, Charlevoix-Saguenay type (Wang, 2021; Chen, 2022). Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Sep 29, 2024