NM_003119.4(SPG7):c.1045G>A (p.Gly349Ser) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000198037.39

Allele description [Variation Report for NM_003119.4(SPG7):c.1045G>A (p.Gly349Ser)]

NM_003119.4(SPG7):c.1045G>A (p.Gly349Ser)

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.1045G>A (p.Gly349Ser)

Other names:

p.G349S:GGC>AGC

HGVS:

NC_000016.10:g.89531961G>A
NG_008082.1:g.28565G>A
NM_001363850.1:c.1045G>A
NM_003119.4:c.1045G>AMANE SELECT
NM_199367.3:c.1045G>A
NP_001350779.1:p.Gly349Ser
NP_003110.1:p.Gly349Ser
NP_955399.1:p.Gly349Ser
NC_000016.9:g.89598369G>A
NM_003119.2:c.1045G>A
NM_003119.3:c.1045G>A
Q9UQ90:p.Gly349Ser

Protein change:

G349S; GLY349SER

Links:

UniProtKB: Q9UQ90#VAR_063607; OMIM: 602783.0010; dbSNP: rs141659620

NCBI 1000 Genomes Browser:

rs141659620

Molecular consequence:

NM_001363850.1:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003119.4:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199367.3:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252337	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 13, 2023)	germline	clinical testing	Citation Link,
SCV000844090	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Oct 26, 2021)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 22964162, 26626314, 21623769, 25034272, 23733235, 23812641, 23269439, 18799786, 20186691, 30747022, 25133958, 23065789, 27790088, 32447552, 26467025
SCV000855030	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Likely pathogenic (May 22, 2018)	germline	clinical testing	Citation Link,
SCV001246893	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV001448118	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001973746	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002035810	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002520064	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	15	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.

van Gassen KL, van der Heijden CD, de Bot ST, den Dunnen WF, van den Berg LH, Verschuuren-Bemelmans CC, Kremer HP, Veldink JH, Kamsteeg EJ, Scheffer H, van de Warrenburg BP.

Brain. 2012 Oct;135(Pt 10):2994-3004. doi: 10.1093/brain/aws224. Epub 2012 Sep 10.

PubMed [citation]

PMID:: 22964162

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.

Choquet K, Tétreault M, Yang S, La Piana R, Dicaire MJ, Vanstone MR, Mathieu J, Bouchard JP, Rioux MF, Rouleau GA; Care4Rare Canada Consortium., Boycott KM, Majewski J, Brais B.

Eur J Hum Genet. 2016 Jul;24(7):1016-21. doi: 10.1038/ejhg.2015.240. Epub 2015 Dec 2.

PubMed [citation]

PMID:: 26626314
PMCID:: PMC5070891

See all PubMed Citations (16)

Details of each submission

From GeneDx, SCV000252337.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported as heterozygous in an individual with HSP in whom a second variant was not described (Brugman et al., 2008); Functional studies performed in yeast cells found that G349S perturbs the function of the SPG7 protein (Bonn et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27016405, 29431110, 32816195, 34662886, 34758253, 23065789, 23269439, 18799786, 21623769, 23733235, 25133958, 26626314, 25034272, 23812641, 30747022, 32447552, 31980526, 32270516, 31589614, 33300680, 33157434, 33841295, 34531397, 30533525, 27790088, 22571692, 22964162, 20186691)

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

From Athena Diagnostics, SCV000844090.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiment showed impaired ATPase activity (PMID:20186691). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure.

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

From Eurofins Ntd Llc (ga), SCV000855030.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	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		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246893.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	not provided

Description

SPG7: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		15	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001448118.1

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

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002035810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV002520064.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

PS3, PS4, PM2, PM3_strong, PP3

#	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		3	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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