NM_003119.4(SPG7):c.1996G>C (p.Gly666Arg) AND Hereditary spastic paraplegia 7

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 13, 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:: RCV000200425.8

Allele description [Variation Report for NM_003119.4(SPG7):c.1996G>C (p.Gly666Arg)]

NM_003119.4(SPG7):c.1996G>C (p.Gly666Arg)

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.1996G>C (p.Gly666Arg)

HGVS:

NC_000016.10:g.89553853G>C
NG_008082.1:g.50457G>C
NM_001363850.1:c.1996G>C
NM_003119.4:c.1996G>CMANE SELECT
NP_001350779.1:p.Gly666Arg
NP_003110.1:p.Gly666Arg
NC_000016.9:g.89620261G>C
NM_003119.2:c.1996G>C
NM_003119.3:c.1996G>C

Protein change:

G666R

Links:

dbSNP: rs752989523

NCBI 1000 Genomes Browser:

rs752989523

Molecular consequence:

NM_001363850.1:c.1996G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003119.4:c.1996G>C - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254783	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23733235, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254783

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort.

Yoon G, Baskin B, Tarnopolsky M, Boycott KM, Geraghty MT, Sell E, Goobie S, Meschino W, Banwell B, Ray PN.

Neurogenetics. 2013 Nov;14(3-4):181-8. doi: 10.1007/s10048-013-0366-9. Epub 2013 Jun 4.

PubMed [citation]

PMID:: 23733235

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, SCV000254783.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 666 of the SPG7 protein (p.Gly666Arg). This variant is present in population databases (rs752989523, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 216571). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23733235; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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