VCV000095851.65 - ClinVar

NM_152564.5(VPS13B):c.3866C>G (p.Thr1289Ser)

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.

(10)

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(3); Benign(1); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152564.5(VPS13B):c.3866C>G (p.Thr1289Ser)

Variation ID: 95851 Accession: VCV000095851.65

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.2 8: 99481798 (GRCh38) [ NCBI UCSC ] 8: 100494026 (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	Jun 29, 2015	May 1, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152564.5:c.3866C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689777.3:p.Thr1289Ser	missense
NM_017890.5:c.3866C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060360.3:p.Thr1289Ser	missense
NC_000008.11:g.99481798C>G
NC_000008.10:g.100494026C>G
NG_007098.2:g.473533C>G
LRG_351:g.473533C>G
LRG_351t1:c.3866C>G	LRG_351p1:p.Thr1289Ser

... more HGVS ... less HGVS

Protein change

T1289S

Other names

Canonical SPDI

NC_000008.11:99481797:C: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.

0.00220 (G)

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

The Genome Aggregation Database (gnomAD), exomes 0.00040

Exome Aggregation Consortium (ExAC) 0.00051

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146

The Genome Aggregation Database (gnomAD) 0.00178

Trans-Omics for Precision Medicine (TOPMed) 0.00181

1000 Genomes Project 0.00220

1000 Genomes Project 30x 0.00234

Links

ClinGen: CA223442 dbSNP: rs145569846 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.
VPS13B		-	-	GRCh38 GRCh37	5986	6056

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.
Cohen syndrome	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000530711.32
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Sep 26, 2018	RCV002311681.9
not provided	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Oct 14, 2020	RCV000081898.25

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 benign (Oct 14, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001779477.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Comment: This variant is associated with the following publications: (PMID: 20921020)
Uncertain significance (Sep 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000899082.3 First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023	Comment: VPS13B NM_017890.4 exon 25 p.Thr1289Ser (c.3866C>G): This variant has been reported in the literature as a compound heterozygote (in trans with a multi-exon deletion of … (more) VPS13B NM_017890.4 exon 25 p.Thr1289Ser (c.3866C>G): This variant has been reported in the literature as a compound heterozygote (in trans with a multi-exon deletion of this gene) in 1 individual with a diagnosis of Cohen syndrome (Rivera-Brugues 2011 PMID:20921020, gene identified as alternate name COH1). However, this variant is present in 0.5% (125/24018) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs145569846). This variant is present in ClinVar (Variation ID:95851). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001137683.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Uncertain significance (Aug 06, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003820434.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Sep 26, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000847118.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 20921020 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Oct 04, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000113833.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015	Publications: PubMed (1) PubMed: 20921020 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VPS13B Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000630874.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Cohen syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456848.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958134.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975329.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021

Comment:

VPS13B NM_017890.4 exon 25 p.Thr1289Ser (c.3866C>G): This variant has been reported in the literature as a compound heterozygote (in trans with a multi-exon deletion of this gene) in 1 individual with a diagnosis of Cohen syndrome (Rivera-Brugues 2011 PMID:20921020, gene identified as alternate name COH1). However, this variant is present in 0.5% (125/24018) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs145569846). This variant is present in ClinVar (Variation ID:95851). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Cohen syndrome diagnosis using whole genome arrays.	Rivera-Brugués N	Journal of medical genetics	2011	PMID: 20921020
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VPS13B	-	-	-	-

Text-mined citations for rs145569846 ...

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 Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_152564.5(VPS13B):c.3866C>G (p.Thr1289Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145569846 ...