NM_025137.4(SPG11):c.3425C>G (p.Ser1142Cys) AND Spastic paraplegia 11, autosomal recessive

Clinical significance:Uncertain significance (Last evaluated: Jun 23, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000462305.7

Allele description [Variation Report for NM_025137.4(SPG11):c.3425C>G (p.Ser1142Cys)]

NM_025137.4(SPG11):c.3425C>G (p.Ser1142Cys)

Gene:
SPG11:SPG11 vesicle trafficking associated, spatacsin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.1
Genomic location:
Preferred name:
NM_025137.4(SPG11):c.3425C>G (p.Ser1142Cys)
HGVS:
  • NC_000015.10:g.44608472G>C
  • NG_008885.1:g.60207C>G
  • NM_001160227.2:c.3425C>G
  • NM_025137.4:c.3425C>GMANE SELECT
  • NP_001153699.1:p.Ser1142Cys
  • NP_079413.3:p.Ser1142Cys
  • NC_000015.9:g.44900670G>C
  • NM_025137.3:c.3425C>G
  • p.Ser1142Cys
Protein change:
S1142C
Links:
dbSNP: rs201082396
NCBI 1000 Genomes Browser:
rs201082396
Molecular consequence:
  • NM_001160227.2:c.3425C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_025137.4:c.3425C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Spastic paraplegia 11, autosomal recessive (SPG11)
Synonyms:
SPASTIC PARAPLEGIA, AUTOSOMAL RECESSIVE, COMPLICATED, WITH THIN CORPUS CALLOSUM; SPASTIC PARAPLEGIA, AUTOSOMAL RECESSIVE, WITH MENTAL IMPAIRMENT AND THIN CORPUS CALLOSUM; Spastic paraplegia 11; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011445; MedGen: C1858479; Orphanet: 2822; OMIM: 604360

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000545208Invitaecriteria provided, single submitter
Uncertain significance
(Jun 23, 2020)
germlineclinical testing

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

SCV001277237Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

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, SCV000545208.6

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

Description

This sequence change replaces serine with cysteine at codon 1142 of the SPG11 protein (p.Ser1142Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs201082396, ExAC 0.02%). This variant has not been reported in the literature in individuals with SPG11-related disease. ClinVar contains an entry for this variant (Variation ID: 406532). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

From Illumina Clinical Services Laboratory,Illumina, SCV001277237.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

Last Updated: Nov 20, 2021

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