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NM_003119.4(SPG7):c.1033G>C (p.Ala345Pro) AND Hereditary spastic paraplegia 7

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Aug 31, 2021
Review status:
criteria provided, conflicting classifications
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:
RCV000501596.12

Allele description [Variation Report for NM_003119.4(SPG7):c.1033G>C (p.Ala345Pro)]

NM_003119.4(SPG7):c.1033G>C (p.Ala345Pro)

Gene:
SPG7:SPG7 matrix AAA peptidase subunit, paraplegin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_003119.4(SPG7):c.1033G>C (p.Ala345Pro)
HGVS:
  • NC_000016.10:g.89531949G>C
  • NG_008082.1:g.28553G>C
  • NM_001363850.1:c.1033G>C
  • NM_003119.4:c.1033G>CMANE SELECT
  • NM_199367.3:c.1033G>C
  • NP_001350779.1:p.Ala345Pro
  • NP_003110.1:p.Ala345Pro
  • NP_955399.1:p.Ala345Pro
  • NC_000016.9:g.89598357G>C
  • NM_003119.2:c.1033G>C
  • NM_003119.3:c.1033G>C
Protein change:
A345P
Links:
dbSNP: rs368373840
NCBI 1000 Genomes Browser:
rs368373840
Molecular consequence:
  • NM_001363850.1:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003119.4:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199367.3:c.1033G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Hereditary spastic paraplegia 7 (SPG7)
Synonyms:
Spastic paraplegia 7; Hereditary spastic paraplegia Paraplegin type; Autosomal recessive spastic paraplegia type 7
Identifiers:
MONDO: MONDO:0011803; MedGen: C1846564; Orphanet: 99013; OMIM: 607259

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000597233Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Dec 23, 2016)
germlineclinical testing

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

SCV001451040Paris Brain Institute, Inserm - ICM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicunknownclinical testing

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

SCV002306598Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Aug 31, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes2not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.

Sun M, Johnson AK, Nelakuditi V, Guidugli L, Fischer D, Arndt K, Ma L, Sandford E, Shakkottai V, Boycott K, Warman-Chardon J, Li Z, Del Gaudio D, Burmeister M, Gomez CM, Waggoner DJ, Das S.

Genet Med. 2019 Jan;21(1):195-206. doi: 10.1038/s41436-018-0007-7. Epub 2018 Jun 18.

PubMed [citation]
PMID:
29915382
PMCID:
PMC6524765
See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000597233.1

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

From Paris Brain Institute, Inserm - ICM, SCV001451040.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided2not providednot providednot provided

From Invitae, SCV002306598.2

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

Description

This sequence change replaces alanine with proline at codon 345 of the SPG7 protein (p.Ala345Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of SPG7-related conditions (PMID: 29915382). ClinVar contains an entry for this variant (Variation ID: 436844). 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 SPG7 protein function. 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: May 7, 2024