NM_018668.5(VPS33B):c.1509dup (p.Lys504fs) AND Arthrogryposis, renal dysfunction, and cholestasis 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002052135.2

Allele description [Variation Report for NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)]

NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)

Gene:

VPS33B:VPS33B late endosome and lysosome associated [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)

HGVS:

NC_000015.10:g.91000562dup
NG_012162.1:g.27042dup
NM_001289148.1:c.1428dup
NM_001289149.1:c.1236dup
NM_018668.5:c.1509dupMANE SELECT
NP_001276077.1:p.Lys477fs
NP_001276078.1:p.Lys413fs
NP_061138.3:p.Lys504fs
LRG_884:g.27042dup
NC_000015.9:g.91543792dup
NM_018668.4:c.109dupG

Protein change:

K413fs

Links:

OMIM: 608552.0012; dbSNP: rs1209349503

NCBI 1000 Genomes Browser:

rs1209349503

Molecular consequence:

NM_001289148.1:c.1428dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001289149.1:c.1236dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_018668.5:c.1509dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Arthrogryposis, renal dysfunction, and cholestasis 1 (ARCS1)
Identifiers:: MONDO: MONDO:0008822; MedGen: C1859722; Orphanet: 2697; OMIM: 208085

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002318619	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18853461, 25741868
SCV002564412	OMIM	no assertion criteria provided	Pathogenic (Aug 18, 2022)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002318619

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002564412

OMIM

no assertion criteria provided

Pathogenic
(Aug 18, 2022)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome.

Cullinane AR, Straatman-Iwanowska A, Seo JK, Ko JS, Song KS, Gizewska M, Gruszfeld D, Gliwicz D, Tuysuz B, Erdemir G, Sougrat R, Wakabayashi Y, Hinds R, Barnicoat A, Mandel H, Chitayat D, Fischler B, Garcia-Cazorla A, Knisely AS, Kelly DA, Maher ER, Gissen P.

Hum Mutat. 2009 Feb;30(2):E330-7. doi: 10.1002/humu.20900.

PubMed [citation]

PMID:: 18853461
PMCID:: PMC2635429

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From 3billion, SCV002318619.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is not observed in the gnomAD v2.1.1 dataset. This variant has been reported to be associated with VPS33B related disorder (PMID:18853461). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV002564412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Progressive Familial Intrahepatic Cholestasis 12

For discussion of the 1-bp duplication (c.109dupG, NM_018668.4) in the VPS33B gene, causing a frameshift predicted to result in a premature termination codon (Lys504GlufsTer), that was found in compound heterozygous state in a Chinese brother (P2) and sister (P3) with isolated cholestasis (PFIC12; 610010) by Qiu et al. (2019), see 608552.0011.

Arthrogryposis, Renal Dysfunction, and Cholestasis 1

In a Chinese female infant (P4) who died at the age of 6 months with arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1; 208085), Qiu et al. (2019) identified compound heterozygosity for the c.109dupG mutation and a splice site mutation (c.403+2T-A; 608552.0013).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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