rs180177365

Variant names:

• chr8-99642435-C-T
• rs180177365
• NM_017890.5:c.5920C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152564.5(VPS13B):​c.5845C>T​(p.Arg1949*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: VPS13B NM_152564.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99642435-C-T is Pathogenic according to our data. Variant chr8-99642435-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99642435-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.5920C>T	p.Arg1974*	stop_gained	Exon 34 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.5845C>T	p.Arg1949*	stop_gained	Exon 34 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.5920C>T	p.Arg1974*	stop_gained	Exon 34 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.5845C>T	p.Arg1949*	stop_gained	Exon 34 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250916 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Mar 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Cohen syndrome referred for genetic testing at GeneDx and in published literature (PMID: 16648375); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16648375) -

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SNPedia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS13B p.R1974* variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Cohen syndrome (Seifert_2006_PMID:16648375). The variant was identified in dbSNP (ID: rs180177365) and ClinVar (classified as pathogenic by Athena Diagnostics Inc, GeneDx and SNPedia). The variant was identified in control databases in 4 of 250916 chromosomes at a frequency of 0.00001594 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 2 of 34476 chromosomes (freq: 0.000058) and European (non-Finnish) in 2 of 113478 chromosomes (freq: 0.000018), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.5920C>T variant leads to a premature stop codon at position 1974 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the VPS13B gene are an established mechanism of disease in Cohen syndrome and is the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

May 06, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Cohen syndrome Pathogenic:4

Oct 25, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VPS13B c.5920C>T (p.Arg1974X) 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 allele was found at a frequency of 1.6e-05 in 250916 control chromosomes (gnomAD). c.5920C>T has been reported in the literature in at least one compound heterozygous individual affected with Cohen Syndrome (Seifert_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 18, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 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.Arg1974*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs180177365, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 16648375, 19006247). ClinVar contains an entry for this variant (Variation ID: 68089). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
Vest4		0.88
GERP RS		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177365; hg19: chr8-100654663; COSMIC: COSV62149913; COSMIC: COSV62149913;