rs786204456

chr8-99875502-CCCAGCTGTTCT-CG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017890.5(VPS13B):c.11906_11916delinsG(p.Pro3969ArgfsTer41) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.58

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]

COX6C (HGNC:2285): (cytochrome c oxidase subunit 6C) Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIc, which has 77% amino acid sequence identity with mouse subunit VIc. This gene is up-regulated in prostate cancer cells. A pseudogene has been found on chromosomes 16p12. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99875503-CCAGCTGTTCT-G is Pathogenic according to our data. Variant chr8-99875503-CCAGCTGTTCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.11906_11916delinsG	p.Pro3969ArgfsTer41	frameshift_variant	62/62	ENST00000358544.7
VPS13B	NM_152564.5	c.11831_11841delinsG	p.Pro3944ArgfsTer41	frameshift_variant	62/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.11831_11841delinsG	p.Pro3944ArgfsTer41	frameshift_variant	62/62	1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.11906_11916delinsG	p.Pro3969ArgfsTer41	frameshift_variant	62/62	1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 29, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2022	Variant summary: VPS13B c.11906_11916delinsG (p.Pro3969ArgfsX41) 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. The variant allele was found at a frequency of 6.3e-06 in 318714 control chromosomes (gnomAD and Haque_2016). c.11906_11916delinsG has been reported in the literature in one individual who was undergoing whole gnomic sequencing (Reuter_2018). The report does not provide unequivocal conclusions about association of the variant with Cohen Syndrome. However, VPS13B c.11906_11915delCCAGCTGTTC, resulting in a similar mutant protein (p.Pro3969LeufsX41), has been reported in one patient with Cohen Syndrome (Kolehmainen_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical-significance assessments for this variant have been submitted to ClinVar after 2014. One classified the variant as pathogenic and the other as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2017

The c.11906_11916del11insG variant in the VPS13B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11906_11916del11insG variant causes a frameshift starting with codon Proline 3969, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Pro3969ArgfsX41. This variant is predicted to cause loss of normal protein function through protein truncation. The c.11906_11916del11insG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.11906_11916del11insG as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204456; hg19: chr8-100887731;