VCV000005275.3 - ClinVar

NM_006946.4(SPTBN2):c.758T>C (p.Leu253Pro)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (1)

1 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006946.4(SPTBN2):c.758T>C (p.Leu253Pro)

Variation ID: 5275 Accession: VCV000005275.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.2 11: 66713645 (GRCh38) [ NCBI UCSC ] 11: 66481116 (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	Aug 31, 2013	Apr 13, 2025	Sep 15, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_006946.4:c.758T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008877.2:p.Leu253Pro	missense
NC_000011.10:g.66713645A>G
NC_000011.9:g.66481116A>G
NG_016150.2:g.20717T>C
	O15020:p.Leu253Pro

... more HGVS ... less HGVS

Protein change

L253P

Other names

Canonical SPDI

NC_000011.10:66713644:A:G

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

ClinGen: CA253456 UniProtKB: O15020#VAR_026767 OMIM: 604985.0003 dbSNP: rs121918306 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.
SPTBN2		-	-	GRCh38 GRCh37	1418	1433

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.
Spinocerebellar ataxia type 5	Pathogenic (1)	no assertion criteria provided	Sep 15, 2010	RCV000005593.4
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 15, 2021	RCV001682706.3

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.	Expand all rows Collapse all rows 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.
Pathogenic (Sep 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal dominant inheritance)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905640.2 First in ClinVar: Sep 25, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Ataxia (present) Sex: female

Pathogenic (Sep 15, 2010) N Not contributing to aggregate classification	no assertion criteria provided	SPINOCEREBELLAR ATAXIA 5	OMIM Accession: SCV000025775.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 31, 2013	Publications: PubMed (2) PubMed: 16429157‚ 20603325 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a German family, Ikeda et al. (2006) found that spinocerebellar ataxia (SCA5; 600224) was related to a T-to-C transition (758T-C) in exon 7 of … (more) In a German family, Ikeda et al. (2006) found that spinocerebellar ataxia (SCA5; 600224) was related to a T-to-C transition (758T-C) in exon 7 of the SPTBN2 gene that caused a leucine-to-proline change (L253P) in the calponin homology domain containing the actin/ARP1 (see 605143)-binding site. Clarkson et al. (2010) introduced the L253P mutation into rat Spnb3 and found that the mutant protein was not targeted to the plasma membrane of transfected cells but was retained in the Golgi compartment. Mutant Spnb3 did not interact with Arp1 (605143), prevented correct localization of the wildtype protein, and caused Golgi accumulation of Eaat4 (600637), preventing it from reaching the plasma membrane. These data provided evidence for a dominant-negative effect of the mutation. (less)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Beta-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi.	Clarkson YL	Human molecular genetics	2010	PMID: 20603325
Spectrin mutations cause spinocerebellar ataxia type 5.	Ikeda Y	Nature genetics	2006	PMID: 16429157

Text-mined citations for rs121918306 ...

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 Apr 13, 2026