NM_022575.4(VPS16):c.2272-18C>A AND See cases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 22, 2023
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:: RCV003128468.8

Allele description [Variation Report for NM_022575.4(VPS16):c.2272-18C>A]

NM_022575.4(VPS16):c.2272-18C>A

Genes:

VPS16:VPS16 core subunit of CORVET and HOPS complexes [Gene - OMIM - HGNC]
PTPRA:protein tyrosine phosphatase receptor type A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p13

Genomic location:

Preferred name:

NM_022575.4(VPS16):c.2272-18C>A

HGVS:

NC_000020.11:g.2866194C>A
NM_002836.4:c.-129+877C>A
NM_022575.4:c.2272-18C>AMANE SELECT
NM_080413.3:c.1840-18C>A
NC_000020.10:g.2846840C>A
NM_022575.3:c.2272-18C>A

Molecular consequence:

NM_002836.4:c.-129+877C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_022575.4:c.2272-18C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_080413.3:c.1840-18C>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: See cases [See the Variation display for details]
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003804383	Clinical Genetics Laboratory, Sahlgrenska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 22, 2023)	biparental	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33938619, 36153662, 36088199, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003804383

Clinical Genetics Laboratory, Sahlgrenska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 22, 2023)

biparental

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.

Sofou K, Meier K, Sanderson LE, Kaminski D, Montoliu-Gaya L, Samuelsson E, Blomqvist M, Agholme L, Gärtner J, Mühlhausen C, Darin N, Barakat TS, Schlotawa L, van Ham T, Asin Cayuela J, Sterky FH.

EMBO Mol Med. 2021 May 7;13(5):e13376. doi: 10.15252/emmm.202013376. Epub 2021 May 3.

PubMed [citation]

PMID:: 33938619
PMCID:: PMC8103096

Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.

Pavlova EV, Lev D, Michelson M, Yosovich K, Michaeli HG, Bright NA, Manna PT, Dickson VK, Tylee KL, Church HJ, Luzio JP, Cox TM.

Hum Mutat. 2022 Dec;43(12):2265-2278. doi: 10.1002/humu.24479. Epub 2022 Oct 8.

PubMed [citation]

PMID:: 36153662
PMCID:: PMC10091966

See all PubMed Citations (4)

Details of each submission

From Clinical Genetics Laboratory, Sahlgrenska University Hospital, SCV003804383.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

The c.2272-18C>A variant in VPS16 has been reported in homozygous form in 2 independent patients of Iranian and Turkish descent, respectively, presenting with progressive psychomotor regression, delayed myelination and mucopolysaccharidosis-like features. The variant is absent from large population databases and predicted to create a splice-acceptor site 16 bp upstream of exon 23 which competes with the normal splice site. This effect has been experimentally confirmed by analysis of cDNA obtained from blood leukocytes. Functional studies in patient-derived fibroblasts demonstrate that the effect on mRNA splicing leads to a ca. 85% reduction of wild type mRNA and VPS16 protein levels. Other HOPS/CORVET subunits, including VPS33A, are similarly reduced . In addition, patient-derived fibroblasts show signs of impaired endocytosis and autophagy as expected from the observed decreased levels of HOPS/CORVET complexes. All these anomalies are rescued upon lentiviral re-expression of VPS16 (Sofou 2021). Based on the above, the c.2272-18C>A variant meets the following ACMG criteria: PS3 and PM2 and consequently is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: May 19, 2024

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