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NM_014946.4(SPAST):c.1348A>G (p.Arg450Gly) AND Hereditary spastic paraplegia 4

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Feb 20, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000644893.13

Allele description [Variation Report for NM_014946.4(SPAST):c.1348A>G (p.Arg450Gly)]

NM_014946.4(SPAST):c.1348A>G (p.Arg450Gly)

Gene:
SPAST:spastin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p22.3
Genomic location:
Preferred name:
NM_014946.4(SPAST):c.1348A>G (p.Arg450Gly)
HGVS:
  • NC_000002.12:g.32136903A>G
  • NG_008730.1:g.78293A>G
  • NM_001363823.2:c.1345A>G
  • NM_001363875.2:c.1249A>G
  • NM_001377959.1:c.1252A>G
  • NM_014946.4:c.1348A>GMANE SELECT
  • NM_199436.2:c.1252A>G
  • NP_001350752.1:p.Arg449Gly
  • NP_001350804.1:p.Arg417Gly
  • NP_001364888.1:p.Arg418Gly
  • NP_055761.2:p.Arg450Gly
  • NP_055761.2:p.Arg450Gly
  • NP_955468.1:p.Arg418Gly
  • LRG_714t1:c.1348A>G
  • LRG_714:g.78293A>G
  • LRG_714p1:p.Arg450Gly
  • NC_000002.11:g.32361972A>G
  • NM_014946.3:c.1348A>G
Protein change:
R417G
Links:
dbSNP: rs1553318223
NCBI 1000 Genomes Browser:
rs1553318223
Molecular consequence:
  • NM_001363823.2:c.1345A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363875.2:c.1249A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377959.1:c.1252A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014946.4:c.1348A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199436.2:c.1252A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary spastic paraplegia 4
Synonyms:
Spastic paraplegia 4, autosomal dominant; Familial spastic paraplegia autosomal dominant 2
Identifiers:
MONDO: MONDO:0008438; MedGen: C1866855; Orphanet: 100985; OMIM: 182601

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000766611Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jun 9, 2022)
germlineclinical testing

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

SCV002061744Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Dec 1, 2021)
germlineclinical testing

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

SCV004012071Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 20, 2024)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males.

Proukakis C, Moore D, Labrum R, Wood NW, Houlden H.

J Neurol Sci. 2011 Jul 15;306(1-2):62-5. doi: 10.1016/j.jns.2011.03.043. Epub 2011 May 5. Review.

PubMed [citation]
PMID:
21546041

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000766611.4

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

Description

This missense change has been observed in individuals with clinical features of spastic paraplegia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg450 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 21546041; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 536442). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 450 of the SPAST protein (p.Arg450Gly).

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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061744.2

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

Description

PM5, PM2, PM1, PP3

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

From Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital, SCV004012071.2

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

Description

This variant has been detected in an affected individual and segregation study on both parents confirmed the variant to be de novo. In silico analysis by REVEL suggests this variant to be damaging (REVEL: 0.898). It is located in the critical core ATPase AAA-type domain (IPR003959) and in a mutational hot spot. The variation is absent in control population (GnomAD). Another amino acid changes in the same residue location has been observed in individuals with HSP (PMID: 21546041).

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

Last Updated: Mar 10, 2024