VCV001878642.5 - ClinVar

NM_015087.5(SPART):c.696dup (p.Val233fs)

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.

(3)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015087.5(SPART):c.696dup (p.Val233fs)

Variation ID: 1878642 Accession: VCV001878642.5

Type and length

Duplication, 1 bp

Location

Cytogenetic: 13q13.3 13: 36335134-36335135 (GRCh38) [ NCBI UCSC ] 13: 36909271-36909272 (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	Jan 21, 2023	Feb 14, 2024	Nov 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015087.5:c.696dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055902.1:p.Val233fs	frameshift
NM_001142294.2:c.696dup	NP_001135766.1:p.Val233fs	frameshift
NM_001142295.2:c.696dup	NP_001135767.1:p.Val233fs	frameshift
NM_001142296.2:c.696dup	NP_001135768.1:p.Val233fs	frameshift
NM_015087.4:c.696dup
NM_015087.4:c.696dupT
NC_000013.11:g.36335142dup
NC_000013.10:g.36909279dup
NG_011559.2:g.40046dup

... more HGVS ... less HGVS

Protein change

V233fs

Other names

Canonical SPDI

NC_000013.11:36335134:AAAAAAAA:AAAAAAAAA

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.

Links

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.
SPART		-	-	GRCh38 GRCh37	347	401

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.
Troyer syndrome	Likely pathogenic (1)	criteria provided, single submitter	-	RCV002510733.2
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 19, 2023	RCV002571603.4

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Troyer syndrome Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820287.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023	Comment: The frameshift duplication p.V233Cfs8 in SPG20 (NM_015087.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The … (more) The frameshift duplication p.V233Cfs8 in SPG20 (NM_015087.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.V233Cfs*8 variant is observed in 2/1,13,524 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing in SPG20. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Failure to thrive (present) , Global developmental delay (present) , Motor delay (present) , Difficulty walking (present) , Choreoathetosis (present) , Cognitive impairment (present) , … (more) Failure to thrive (present) , Global developmental delay (present) , Motor delay (present) , Difficulty walking (present) , Choreoathetosis (present) , Cognitive impairment (present) , Muscle weakness (present) , Slurred speech (present) (less)
Likely pathogenic (Feb 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004030585.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge (less)
Pathogenic (Nov 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003449446.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 18413476‚ 20437587‚ 20504295 Comment: This sequence change creates a premature translational stop signal (p.Val233Cysfs8) in the SPART gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Val233Cysfs8) in the SPART gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPART are known to be pathogenic (PMID: 18413476, 20437587, 20504295). This variant is present in population databases (rs770560051, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SPART-related conditions. ClinVar contains an entry for this variant (Variation ID: 1878642). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The frameshift duplication p.V233Cfs*8 in SPG20 (NM_015087.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.V233Cfs*8 variant is observed in 2/1,13,524 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing in SPG20. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

Comment:

This sequence change creates a premature translational stop signal (p.Val233Cysfs*8) in the SPART gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPART are known to be pathogenic (PMID: 18413476, 20437587, 20504295). This variant is present in population databases (rs770560051, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SPART-related conditions. ClinVar contains an entry for this variant (Variation ID: 1878642). For these reasons, this variant has been classified as Pathogenic.

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
Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets.	Hooper C	BMC biology	2010	PMID: 20504295
Developmental and degenerative features in a complicated spastic paraplegia.	Manzini MC	Annals of neurology	2010	PMID: 20437587
Lack of spartin protein in Troyer syndrome: a loss-of-function disease mechanism?	Bakowska JC	Archives of neurology	2008	PMID: 18413476

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_015087.5(SPART):c.696dup (p.Val233fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...