VCV000194676.44 - ClinVar

NM_025137.4(SPG11):c.3037A>G (p.Lys1013Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(9); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_025137.4(SPG11):c.3037A>G (p.Lys1013Glu)

Variation ID: 194676 Accession: VCV000194676.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 44615364 (GRCh38) [ NCBI UCSC ] 15: 44907562 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 8, 2017	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025137.4:c.3037A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079413.3:p.Lys1013Glu	missense
NM_001160227.2:c.3037A>G	NP_001153699.1:p.Lys1013Glu	missense
NC_000015.10:g.44615364T>C
NC_000015.9:g.44907562T>C
NG_008885.1:g.53315A>G

... more HGVS ... less HGVS

Protein change

K1013E

Other names

Canonical SPDI

NC_000015.10:44615363:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00439 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00439

1000 Genomes Project 30x 0.00468

The Genome Aggregation Database (gnomAD) 0.00958

Exome Aggregation Consortium (ExAC) 0.00993

The Genome Aggregation Database (gnomAD), exomes 0.01021

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01024

Trans-Omics for Precision Medicine (TOPMed) 0.01053

Links

ClinGen: CA201295 dbSNP: rs111347025 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SPG11		-	-	GRCh38 GRCh37	3257	3358

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000175101.11
Hereditary spastic paraplegia 11	Benign (6)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000204165.24
Amyotrophic lateral sclerosis	Uncertain significance (1)	criteria provided, single submitter	Sep 9, 2020	RCV001260215.3
not provided	Benign (1)	criteria provided, single submitter	Aug 1, 2024	RCV002262769.17
Hereditary spastic paraplegia	Benign (1)	criteria provided, single submitter	Oct 12, 2021	RCV001847810.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 03, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001474772.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (5) PubMed: 27904835‚ 25588603‚ 19466474‚ 23733235‚ 24833714
Likely benign (Dec 10, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051017.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Benign (Oct 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002105701.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545248.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: SPG11: BP4, BS1, BS2 Number of individuals with the variant: 43
Benign (Aug 02, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521190.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Oct 09, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743947.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (Mar 04, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226531.5 First in ClinVar: Jun 28, 2015 Last updated: Mar 08, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SPG11 Number of individuals with the variant: 1 Sex: mixed
Benign (Mar 08, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279400.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 24833714‚ 27904835‚ 25588603‚ 23733235 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary spastic paraplegia 11 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435157.2 First in ClinVar: Oct 03, 2020 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 23733235 Comment: The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), … (more) The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), but has also been identified in >1% of European (non-Finnish) chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for spastic paraplegia. (less)
Uncertain significance (Sep 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Amyotrophic lateral sclerosis Affected status: yes Allele origin: unknown	UM ALS/MND Lab, University Of Malta Accession: SCV001437184.1 First in ClinVar: Oct 08, 2020 Last updated: Oct 08, 2020 Comment: Single heterozygote	Number of individuals with the variant: 1 Age: 30-39 years Sex: male Ethnicity/Population group: Maltese Geographic origin: Malta
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261161.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733443.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Mar 16, 2017)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745910.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924143.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), but has also been identified in >1% of European (non-Finnish) chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for spastic paraplegia.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure.	Fichna JP	BBA clinical	2016	PMID: 27904835
Investigation of next-generation sequencing technologies as a diagnostic tool for amyotrophic lateral sclerosis.	Morgan S	Neurobiology of aging	2015	PMID: 25588603
Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.	Pensato V	Brain : a journal of neurology	2014	PMID: 24833714
Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort.	Yoon G	Neurogenetics	2013	PMID: 23733235
Abstracts of the Nineteenth Meeting of the European Neurological Society. June 20-24, 2009. Milan, Italy.	-	Journal of neurology	2009	PMID: 19466474
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SPG11	-	-	-	-

Text-mined citations for rs111347025 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_025137.4(SPG11):c.3037A>G (p.Lys1013Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111347025 ...