rs386834118

chr8-99823831-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_017890.5(VPS13B):c.9260dup(p.Leu3087PhefsTer20) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS13B NM_017890.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 0.210

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 20 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-99823831-G-GT is Pathogenic according to our data. Variant chr8-99823831-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 2826.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.9260dup	p.Leu3087PhefsTer20	frameshift_variant, splice_region_variant		ENST00000358544.7
VPS13B	NM_152564.5	c.9185dup	p.Leu3062PhefsTer20	frameshift_variant, splice_region_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.9185dup	p.Leu3062PhefsTer20	frameshift_variant, splice_region_variant		1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.9260dup	p.Leu3087PhefsTer20	frameshift_variant, splice_region_variant		1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Leu3087Phefs*20) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15211651). It has also been observed to segregate with disease in related individuals. This variant is also known as c.9258_9259insT. ClinVar contains an entry for this variant (Variation ID: 2826). 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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Leu3087PhefsTer20 variant in VPS13B was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 845268), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 845268). The p.Leu3087PhefsTer20 variant in VPS13B has been previously reported in 2 unrelated individuals with Cohen syndrome and segregated with disease in 8 affected relatives from 2 families (PMID: 15211651). These previously reported individuals were homozygotes (PMID: 15211651), which increases the likelihood that the p.Leu3087PhefsTer20 variant is pathogenic. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 2826) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3087 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3, PP1_Strong (Richards 2015). -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2020

The c.9260dupT (p.L3087Ffs*20) alteration, located in exon 51 (coding exon 50) of the VPS13B gene, results from a duplication of one nucleotide at position 9260, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in 8 affected children from an Amish kindred who were homozygous for this alteration (referred to as c.9258_9259dupT); their phenotypes included childhood-onset pigmentary retinopathy, progressive high myopia, global developmental delay, short stature, microcephaly, truncal hypotonia, joint hyperextensibility, small/narrow hands and feet, and dysmorphic facial features (Falk, 2004). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

SNPedia

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: 0
DS_AL_spliceai		0.89		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177329; hg19: chr8-100836059;