ClinVar Genomic variation as it relates to human health
NM_152564.5(VPS13B):c.7366G>A (p.Val2456Ile)
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.
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.
Uncertain significance(4); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_152564.5(VPS13B):c.7366G>A (p.Val2456Ile)
Variation ID: 95865 Accession: VCV000095865.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8q22.2 8: 99776893 (GRCh38) [ NCBI UCSC ] 8: 100789121 (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 Mar 29, 2015 Oct 8, 2024 Feb 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_152564.5:c.7366G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689777.3:p.Val2456Ile missense NM_017890.5:c.7441G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060360.3:p.Val2481Ile missense NM_152564.4:c.7366G>A NC_000008.11:g.99776893G>A NC_000008.10:g.100789121G>A NG_007098.2:g.768628G>A LRG_351:g.768628G>A LRG_351t1:c.7441G>A LRG_351p1:p.Val2481Ile LRG_351t2:c.7366G>A Q7Z7G8:p.Val2481Ile - Protein change
- V2456I
- Other names
- -
- Canonical SPDI
- NC_000008.11:99776892:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00023
The Genome Aggregation Database (gnomAD) 0.00027
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00017
1000 Genomes Project 0.00020
- Links
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 | ||
---|---|---|---|---|---|---|
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 |
5960 | 6030 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 29, 2024 | RCV000169023.23 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 13, 2024 | RCV000081912.16 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 2, 2022 | RCV002222383.9 | |
Likely benign (1) |
criteria provided, single submitter
|
Jun 15, 2017 | RCV002381403.9 | |
VPS13B-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Jul 2, 2024 | RCV003398677.6 |
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
(Aug 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000113847.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cohen syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001137685.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Uncertain significance
(Mar 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500561.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: VPS13B c.7441G>A (p.Val2481Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: VPS13B c.7441G>A (p.Val2481Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00017 vs 0.0025), allowing no conclusion about variant significance. c.7441G>A has been reported in the literature as a homozygous genotype in an individual who underwent diagnostic exome sequencing for severe intellectual disability (example, de Ligt_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Likely benign
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cohen syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000821255.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Jun 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002671681.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
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
(Feb 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201581.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23033978, 35690661)
|
|
Uncertain significance
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cohen syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000470823.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
Likely benign
(Mar 14, 2014)
|
criteria provided, single submitter
Method: literature only
|
Cohen syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220170.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Uncertain significance
(Jul 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
VPS13B-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004119311.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The VPS13B c.7366G>A variant is predicted to result in the amino acid substitution p.Val2456Ile. This variant, which is referred to as c.7441G>A (p.Val2481Ile) on an … (more)
The VPS13B c.7366G>A variant is predicted to result in the amino acid substitution p.Val2456Ile. This variant, which is referred to as c.7441G>A (p.Val2481Ile) on an alternative transcript (NM_017890), has been reported in the homozygous state in an individual with severe intellectual disability (Table S9, de Ligt et al. 2012. PubMed ID: 23033978). However, several other homozygous variants in other genes were identified in this individual and it is not clear if this variant was contributing to the phenotypes. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Diagnostic exome sequencing in persons with severe intellectual disability. | de Ligt J | The New England journal of medicine | 2012 | PMID: 23033978 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VPS13B | - | - | - | - |
Text-mined citations for rs201963516 ...
HelpRecord last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.