NM_014363.6(SACS):c.10907G>A (p.Arg3636Gln) AND Spastic paraplegia

Clinical significance:Uncertain significance (Last evaluated: Jul 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001244900.1

Allele description [Variation Report for NM_014363.6(SACS):c.10907G>A (p.Arg3636Gln)]

NM_014363.6(SACS):c.10907G>A (p.Arg3636Gln)

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.10907G>A (p.Arg3636Gln)
HGVS:
  • NC_000013.11:g.23332969C>T
  • NG_012342.1:g.105734G>A
  • NM_001278055.2:c.10466G>A
  • NM_014363.6:c.10907G>AMANE SELECT
  • NP_001264984.1:p.Arg3489Gln
  • NP_055178.3:p.Arg3636Gln
  • NC_000013.10:g.23907108C>T
  • NM_014363.4:c.10907G>A
  • NM_014363.5:c.10907G>A
  • Q9NZJ4:p.Arg3636Gln
Protein change:
R3489Q
Links:
UniProtKB: Q9NZJ4#VAR_064818; dbSNP: rs281865119
NCBI 1000 Genomes Browser:
rs281865119
Molecular consequence:
  • NM_001278055.2:c.10466G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014363.6:c.10907G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Spastic paraplegia
Synonyms:
Spastic paraplegia, lower limb
Identifiers:
MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001418153Invitaecriteria provided, single submitter
Uncertain significance
(Jul 16, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Mutations in SACS cause atypical and late-onset forms of ARSACS.

Baets J, Deconinck T, Smets K, Goossens D, Van den Bergh P, Dahan K, Schmedding E, Santens P, Rasic VM, Van Damme P, Robberecht W, De Meirleir L, Michielsens B, Del-Favero J, Jordanova A, De Jonghe P.

Neurology. 2010 Sep 28;75(13):1181-8. doi: 10.1212/WNL.0b013e3181f4d86c.

PubMed [citation]
PMID:
20876471

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001418153.1

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

Description

This sequence change replaces arginine with glutamine at codon 3636 of the SACS protein (p.Arg3636Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs281865119, ExAC 0.002%). This variant has been observed on the same allele carrying a second variant (c.10954C>A, p.Pro3652Thr) in several families affected with clinical features of autosomal recessive spastic ataxia of Charlevoix-Saguenay in which this allele occurred in the homozygous state or in trans with an additional SACS variant on the opposite allele (PMID: 20876471). ClinVar contains an entry for this variant (Variation ID: 38457). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 16, 2021

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