VCV002430290.1 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 2430290 Accession: VCV002430290.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 2866194 (GRCh38) [ NCBI UCSC ] 20: 2846840 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 5, 2023	Mar 4, 2023	Feb 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022575.4:c.2272-18C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_002836.4:c.-129+877C>A		intron variant
NM_080413.3:c.1840-18C>A		intron variant
NC_000020.11:g.2866194C>A
NC_000020.10:g.2846840C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000020.11:2866193:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PTPRA		-	-	GRCh38 GRCh37	38	128
VPS16		-	-	GRCh38 GRCh37	89	180

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
See cases	Likely pathogenic (1)	criteria provided, single submitter	Feb 22, 2023	RCV003128468.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Clinical Genetics Laboratory, Sahlgrenska University Hospital Accession: SCV003804383.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Publications: PubMed (3) PubMed: 33938619‚ 36153662‚ 36088199 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2 Clinical Features: Progressive psychomotor regression (present) , Delayed myelination (present) , Mucopolysaccharidosis-like features (present) , Neutropenia (present) Sex: mixed

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.	Pavlova EV	Human mutation	2022	PMID: 36153662
Genetic intersection between dystonia and neurodevelopmental disorders: Insights from genomic sequencing.	Dzinovic I	Parkinsonism & related disorders	2022	PMID: 36088199
Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.	Sofou K	EMBO molecular medicine	2021	PMID: 33938619

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...