8-99871656-ACAGTG-AAGAA

Variant names:

• chr8-99871657-CAGTG-AGAA
• rs386834067
• NM_017890.5:c.11780_11784delCAGTGinsAGAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017890.5(VPS13B):​c.11780_11784delCAGTGinsAGAA​(p.Thr3927LysfsTer15) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T3927T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13B NM_017890.5 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.30
• Publications: 1 publications found

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99871657-CAGTG-AGAA is Pathogenic according to our data. Variant chr8-99871657-CAGTG-AGAA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.11780_11784delCAGTGinsAGAA	p.Thr3927LysfsTer15	frameshift_variant, missense_variant	Exon 61 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.11705_11709delCAGTGinsAGAA	p.Thr3902LysfsTer15	frameshift_variant, missense_variant	Exon 61 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.11780_11784delCAGTGinsAGAA	p.Thr3927LysfsTer15	frameshift_variant, missense_variant	Exon 61 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.11705_11709delCAGTGinsAGAA	p.Thr3902LysfsTer15	frameshift_variant, missense_variant	Exon 61 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:4

Jun 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VPS13B c.11780_11784delinsAGAA (p.Thr3927LysfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251434 control chromosomes. c.11780_11784delinsAGAA has been reported in the literature in at-least one individual affected with Cohen Syndrome (example, Seifert_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr3927Lysfs*15) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the VPS13B protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with Cohen syndrome (PMID: 16648375). This variant is also known as two separate variants in cis (c.11780delC and c.11783TG>AA). This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Asn3954Lysfs*60) have been determined to be pathogenic (PMID: 20656880). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Inborn genetic diseases Pathogenic:1

Jan 15, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.11780_11784delCAGTGinsAGAA (p.T3927Kfs*15) alteration, located in exon 61 (coding exon 60) of the VPS13B gene, results from the deletion of 5 nucleotides and insertion of 4 nucleotides at positions 11780 to 11784, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of VPS13B, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last 82 amino acids of the protein and the exact functional impact of these altered amino acids is unknown at this time; however, other frameshift alterations downstream of this alteration have been reported in the in individuals with a phenotype consistent with Cohen syndrome (Kolehmainen, 2004; El Chehadeh, 2010). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the VPS13B c.11780_11784delCAGTGinsAGAA (p.T3927Kfs*15) alteration was observed in 0.0004% (1/251434) of total alleles studied. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported in a patient with suspected Cohen syndrome, whose phenotype included microcephaly, developmental delay, typical facial features, myopia, narrow hands/feet, and neutropenia, and who was heterozygous for a second frameshift alteration (Seifert, 2006). Based on the available evidence, this alteration is classified as likely pathogenic.

VPS13B-related disorder Pathogenic:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS13B c.11705_11709delinsAGAA variant is predicted to result in a frameshift and premature protein termination (p.Thr3902Lysfs*15). This variant has been reported in the compound heterozygous state in an individual with Cohen syndrome (Seifert et al., 2006. PubMed ID: 16648375). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=6/194	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386834067; hg19: chr8-100883885;