NM_001128159.3(VPS53):c.1556+5G>A AND Pontoneocerebellar hypoplasia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 1, 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:: RCV002298475.1

Allele description [Variation Report for NM_001128159.3(VPS53):c.1556+5G>A]

NM_001128159.3(VPS53):c.1556+5G>A

Gene:

VPS53:VPS53 subunit of GARP complex [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.3

Genomic location:

Preferred name:

NM_001128159.3(VPS53):c.1556+5G>A

HGVS:

NC_000017.11:g.562498C>T
NG_034190.1:g.157359G>A
NM_001128159.3:c.1556+5G>AMANE SELECT
NM_001366253.2:c.1556+5G>A
NM_001366254.2:c.962+5G>A
NM_018289.4:c.1469+5G>A
NC_000017.10:g.465738C>T
NM_001128159.2:c.1556+5G>A

Nucleotide change:

IVS14DS, G-A, +5

Links:

OMIM: 615850.0002; dbSNP: rs587777466

NCBI 1000 Genomes Browser:

rs587777466

Molecular consequence:

NM_001128159.3:c.1556+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001366253.2:c.1556+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001366254.2:c.962+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_018289.4:c.1469+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Pontoneocerebellar hypoplasia
Synonyms:: Pontocerebellar hypoplasia; Non-syndromic pontocerebellar hypoplasia
Identifiers:: MONDO: MONDO:0020135; MedGen: C1261175; Orphanet: 98523; OMIM: PS607596

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002598685	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24577744, 30100179 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002598685

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2).

Feinstein M, Flusser H, Lerman-Sagie T, Ben-Zeev B, Lev D, Agamy O, Cohen I, Kadir R, Sivan S, Leshinsky-Silver E, Markus B, Birk OS.

J Med Genet. 2014 May;51(5):303-8. doi: 10.1136/jmedgenet-2013-101823. Epub 2014 Feb 27.

PubMed [citation]

PMID:: 24577744

Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes.

Hady-Cohen R, Ben-Pazi H, Adir V, Yosovich K, Blumkin L, Lerman-Sagie T, Lev D.

Eur J Paediatr Neurol. 2018 Nov;22(6):1133-1138. doi: 10.1016/j.ejpn.2018.07.003. Epub 2018 Jul 26.

PubMed [citation]

PMID:: 30100179

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598685.1

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

Description

Variant summary: VPS53 c.1556+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict it weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant generates an aberrant/unstable transcript (Feinstein_2014). The variant was absent in 251280 control chromosomes (gnomAD). c.1556+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Pontocerebellar Hypoplasia, Type 2E (example, Feinstein_2014 and Hady-Cohen_2018). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024

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