rs386834055

Variant names:

• chr8-99853469-T-TA
• rs386834055
• NM_017890.5:c.10156dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017890.5(VPS13B):​c.10156dupA​(p.Thr3386AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VPS13B NM_017890.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.26
• Publications: 3 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-99853469-T-TA is Pathogenic according to our data. Variant chr8-99853469-T-TA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56629.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.10156dupA	p.Thr3386AsnfsTer3	frameshift_variant	Exon 56 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.10081dupA	p.Thr3361AsnfsTer3	frameshift_variant	Exon 56 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.10156dupA	p.Thr3386AsnfsTer3	frameshift_variant	Exon 56 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.10081dupA	p.Thr3361AsnfsTer3	frameshift_variant	Exon 56 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251138 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000349 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:12

Mar 01, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This inherited recessive pathogenic mutation in the VPS13B gene in combination with a second recessive pathogenic mutation in the same gene, NM_152564.4:c.10165_10207del, was observed in a patient with Cohen syndrome. -

Aug 12, 2019

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.10156dupA (p.Thr3386AsnfsX3) 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 3.6e-05 in 251338 control chromosomes. c.10156dupA has been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012) . These data do not allow any conclusion about variant significance. 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) and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 17, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2019

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 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.Thr3386Asnfs*3) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Cohen Syndrome (PMID: 22855652). ClinVar contains an entry for this variant (Variation ID: 56629). For these reasons, this variant has been classified as Pathogenic. -

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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VPS13B c.10156dupA p.(Thr3386AsnfsTer3) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a splice region variant in an Italian individual with Cohen syndrome who exhibited psychomotor development, severe language impairment, hypotonia, joint laxity, neutropenia, exotropia, macular atrophy, and friendly behavior (Athanasakis et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000196 in the South Asian population (version 2.1.1). Based on the available evidence, the p.(Thr3386AsnfsTer3) variant is classified as pathogenic for Cohen syndrome. -

Apr 24, 2014

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. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift duplication p.T3386Nfs*3 in VPS13B (NM_017890.5) has previously been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012). The variant has been reported to ClinVar as Pathogenic/Likely Pathogenic. The p.T3386Nfs*3 variant is observed in 6/30,610 (0.0196%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The p.T3386Nfs*3 variant is a loss of function variant in the gene VPS13B, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NM_017890.5:c.292-1G>A and 155 others. For these reasons, this variant has been classified as Pathogenic. -

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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous single base pair duplication in exon 56 of the VPS13B gene that results in a frameshift and premature truncation of the protein 3 amino acids downstream to codon 3361 was detected. This variant has not been reported in the 1000 genomes databases. The reference region is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -

not provided Pathogenic:2

Mar 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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; This variant is associated with the following publications: (PMID: 22855652) -

Nov 07, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs386834055; hg19: chr8-100865697;