VCV002664503.5 - ClinVar

NM_005898.5(CAPRIN1):c.1535C>T (p.Pro512Leu)

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.

(4)

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
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005898.5(CAPRIN1):c.1535C>T (p.Pro512Leu)

Variation ID: 2664503 Accession: VCV002664503.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 34090659 (GRCh38) [ NCBI UCSC ] 11: 34112206 (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	Dec 17, 2023	Apr 20, 2024	Mar 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005898.5:c.1535C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005889.3:p.Pro512Leu	missense
NM_203364.3:c.1535C>T	NP_976240.1:p.Pro512Leu	missense
NC_000011.10:g.34090659C>T
NC_000011.9:g.34112206C>T

Protein change

P512L

Other names

NM_203364.3:c.1535C>T

Canonical SPDI

NC_000011.10:34090658:C:T

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

OMIM: 601178.0001 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.
CAPRIN1		-	-	GRCh38 GRCh37	59	78

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.
Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline	Likely pathogenic (2)	criteria provided, single submitter	Mar 3, 2024	RCV003447462.3
Cerebellar ataxia	Uncertain significance (1)	criteria provided, single submitter	Dec 20, 2023	RCV003458924.2
not provided	Uncertain significance (1)	criteria provided, single submitter	May 2, 2022	RCV003488800.2

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 (Dec 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cerebellar ataxia Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: GREGoR Consortium Accession: SCV004190140.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/15bb466b-9a63-4552-bba9-32e6b9aca46e Comment: The heterozygous p.Pro512Leu variant in CAPRIN1 was identified by our study in 1 individual with cerebellar atrophy, ataxia, motor axonal neuropathy, and intellectual disability. While … (more) The heterozygous p.Pro512Leu variant in CAPRIN1 was identified by our study in 1 individual with cerebellar atrophy, ataxia, motor axonal neuropathy, and intellectual disability. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for this phenotype. Given the limited information about this gene-disease relationship, the significance of the p.Pro512Leu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in CAPRIN1 we encourage you to reach out to us. (less)
Uncertain significance (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004234940.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely pathogenic (Mar 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline Affected status: yes Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV004801352.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Publications: PubMed (1) PubMed: 36136249 Comment: This variant is interpreted for Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline. The following ACMG Tag(s) were applied: Absent from controls (or at extremely … (more) This variant is interpreted for Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in gnomAD (PM2). De novo data (PS2). Prevalence in affected individuals statistically increased over controls (PS4-supporting). Well-established functional studies show a deleterious effect (PS3-supporting). (less)
Pathogenic (Apr 11, 2024)	no assertion criteria provided Method: literature only	NEURODEGENERATION, CHILDHOOD-ONSET, WITH CEREBELLAR ATAXIA AND COGNITIVE DECLINE Affected status: not provided Allele origin: germline	OMIM Accession: SCV004174851.2 First in ClinVar: Dec 17, 2023 Last updated: Apr 20, 2024	Publications: PubMed (1) PubMed: 36136249 Comment on evidence: In 2 unrelated patients with childhood-onset neurodegeneration with cerebellar ataxia and cognitive decline (CONDCAC; 620636), Delle Vedove et al. (2022) identified the same de novo … (more) In 2 unrelated patients with childhood-onset neurodegeneration with cerebellar ataxia and cognitive decline (CONDCAC; 620636), Delle Vedove et al. (2022) identified the same de novo heterozygous c.1535C-T transition (c.1535C-T, NM_005898.5) in exon 14 of the CAPRIN1 gene, resulting in a pro512-to-leu (P512L) substitution at a conserved residue near the prion-like domain (PrLD). The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. In vitro studies in HEK293 and SH-SY5Y cells transfected with the mutation showed that the P512L mutant protein formed insoluble ubiquitinated aggregates that stained for SQSTM1 (601530) and sequestered proteins associated with neurodegenerative disorders, including ATXN2, GEMIN5, SNRNP200, and SNCA. Cortical neurons carrying the mutation, generated by CRISPR/Cas9 genome editing of induced pluripotent stem cells (iPSC), did not display protein aggregates, but they had reduced neuronal activity in electrophysiologic studies and showed altered stress granule dynamics. The mutation did not impair CAPRIN1 dimerization, but resulted in an expanded conformation of the protein. CAPRIN1 P521L aggregation was strongly enhanced by RNA in vitro. The findings were consistent with a gain-of-function effect. In a note added in proof, Delle Vedove et al. (2022) stated that they were notified by Gene Matcher of a 14-year-old girl with an identical phenotype and the same de novo CAPRIN1 mutation. (less)

Comment:

The heterozygous p.Pro512Leu variant in CAPRIN1 was identified by our study in 1 individual with cerebellar atrophy, ataxia, motor axonal neuropathy, and intellectual disability. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for this phenotype. Given the limited information about this gene-disease relationship, the significance of the p.Pro512Leu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in CAPRIN1 we encourage you to reach out to us.

Comment:

This variant is interpreted for Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in gnomAD (PM2). De novo data (PS2). Prevalence in affected individuals statistically increased over controls (PS4-supporting). Well-established functional studies show a deleterious effect (PS3-supporting).

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
CAPRIN1(P512L) causes aberrant protein aggregation and associates with early-onset ataxia.	Delle Vedove A	Cellular and molecular life sciences : CMLS	2022	PMID: 36136249
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/15bb466b-9a63-4552-bba9-32e6b9aca46e	-	-	-	-

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_005898.5(CAPRIN1):c.1535C>T (p.Pro512Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...