VCV000216774.16 - ClinVar

NM_025137.4(SPG11):c.7132T>C (p.Phe2378Leu)

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.

(8)

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(6); 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.7132T>C (p.Phe2378Leu)

Variation ID: 216774 Accession: VCV000216774.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 44564566 (GRCh38) [ NCBI UCSC ] 15: 44856764 (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	Apr 9, 2018	Aug 25, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_025137.4:c.7132T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079413.3:p.Phe2378Leu	missense
NM_001160227.2:c.6793T>C	NP_001153699.1:p.Phe2265Leu	missense
NC_000015.10:g.44564566A>G
NC_000015.9:g.44856764A>G
NG_008885.1:g.104113T>C

... more HGVS ... less HGVS

Protein change

F2378L, F2265L

Other names

Canonical SPDI

NC_000015.10:44564565:A:G

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00014

Exome Aggregation Consortium (ExAC) 0.00017

The Genome Aggregation Database (gnomAD) 0.00009

Links

ClinGen: CA337736 dbSNP: rs150571352 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	3265	3367

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.
Hereditary spastic paraplegia 11	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 6, 2022	RCV000198221.11
not specified	Likely benign (1)	criteria provided, single submitter	Feb 5, 2018	RCV000609376.2
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001252105.3
Hereditary spastic paraplegia	Uncertain significance (1)	criteria provided, single submitter	Jan 14, 2020	RCV001847903.4
Amyotrophic lateral sclerosis type 5	Uncertain significance (1)	criteria provided, single submitter	May 5, 2020	RCV001331387.2
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Nov 27, 2023	RCV002363018.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 27, 2023	RCV004696869.1

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.
Uncertain significance (Sep 06, 2022)	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: SCV000255134.8 First in ClinVar: Oct 11, 2015 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 27066562 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2378 of the SPG11 protein (p.Phe2378Leu). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2378 of the SPG11 protein (p.Phe2378Leu). This variant is present in population databases (rs150571352, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 27066562). ClinVar contains an entry for this variant (Variation ID: 216774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. (less)
Likely benign (Feb 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730587.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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)
Uncertain significance (May 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic lateral sclerosis type 5 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001523420.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Jan 14, 2020)	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: SCV002105777.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Uncertain significance (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV002570395.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (4) PubMed: 17322883‚ 18067136‚ 27066562‚ 27217339 Comment: This SPG11 variant (rs150571352) is rare (<0.1%) in a large population dataset (gnomAD: 52/282406 total alleles; 0.02%; no homozygotes) and has been reported in ClinVar. … (more) This SPG11 variant (rs150571352) is rare (<0.1%) in a large population dataset (gnomAD: 52/282406 total alleles; 0.02%; no homozygotes) and has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging while another predicts that it would be tolerated. The phenylalanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 39 splicing, although this has not been confirmed experimentally to our knowledge. This variant was identified in a homozygous state in a single family with juvenile motor neuron disease. However, an additional homozygous nonsense variant in the SPG11 gene (c.2250delT) was also identified in affected family members making the functional impact of c.7132T>C alone unclear. Due to insufficient evidence, we consider the clinical significance of c.7132T>C to be uncertain at this time. (less)
Uncertain significance (Nov 27, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002662286.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 25174650‚ 27066562 Comment: The c.7132T>C (p.F2378L) alteration is located in exon 39 (coding exon 39) of the SPG11 gene. This alteration results from a T to C substitution … (more) The c.7132T>C (p.F2378L) alteration is located in exon 39 (coding exon 39) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 7132, causing the phenylalanine (F) at amino acid position 2378 to be replaced by a leucine (L). The altered amino acid is well conserved throughout evolution:_x000D_ _x000D_ The p.F2378 amino acid is conserved in available primate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.F2378L alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198338.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Uncertain significance (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427854.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2378 of the SPG11 protein (p.Phe2378Leu). This variant is present in population databases (rs150571352, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 27066562). ClinVar contains an entry for this variant (Variation ID: 216774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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 SPG11 variant (rs150571352) is rare (<0.1%) in a large population dataset (gnomAD: 52/282406 total alleles; 0.02%; no homozygotes) and has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging while another predicts that it would be tolerated. The phenylalanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 39 splicing, although this has not been confirmed experimentally to our knowledge. This variant was identified in a homozygous state in a single family with juvenile motor neuron disease. However, an additional homozygous nonsense variant in the SPG11 gene (c.2250delT) was also identified in affected family members making the functional impact of c.7132T>C alone unclear. Due to insufficient evidence, we consider the clinical significance of c.7132T>C to be uncertain at this time.

Comment:

The c.7132T>C (p.F2378L) alteration is located in exon 39 (coding exon 39) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 7132, causing the phenylalanine (F) at amino acid position 2378 to be replaced by a leucine (L). The altered amino acid is well conserved throughout evolution:_x000D_ _x000D_ The p.F2378 amino acid is conserved in available primate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.F2378L alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
Genetic and phenotypic characterization of complex hereditary spastic paraplegia.	Kara E	Brain : a journal of neurology	2016	PMID: 27217339
Turkish families with juvenile motor neuron disease broaden the phenotypic spectrum of SPG11.	Iskender C	Neurology. Genetics	2015	PMID: 27066562
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	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Mutation analysis of patients with neurodegenerative disorders using NeuroX array.	Ghani M	Neurobiology of aging	2015	PMID: 25174650
Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.	Hehr U	Annals of neurology	2007	PMID: 18067136
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.	Stevanin G	Nature genetics	2007	PMID: 17322883

Text-mined citations for rs150571352 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_025137.4(SPG11):c.7132T>C (p.Phe2378Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150571352 ...