VPS13D

protein-coding

vacuolar protein sorting 13 homolog D, the group of bridge-like lipid transfer protein family|Small nucleolar RNA protein coding host genes

Gene summary

This gene encodes a protein belonging to the vacuolar-protein-sorting-13 gene family. In yeast, vacuolar-protein-sorting-13 proteins are involved in trafficking of membrane proteins between the trans-Golgi network and the prevacuolar compartment. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode distinct isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015378.4

Inheritance

ClinVar variants

P:78U:961B:488

Top phenotype

Spinocerebellar ataxia, autosomal recessive 4

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr1:12,230,030-12,512,047

External References & Databases

Ensembl (ENSG00000048707)

Transcript & Mutation Effects

hg38 • Region Span ~282.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: Illumina

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: PanelApp Australia

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between VPS13D and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The VPS13D gene encodes vacuolar protein sorting 13 homolog D, which has been shown to be critical to mitochondrial stability, fission, and clearance by mitophagy. The VPS13D gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2018 (PMID: 29518281). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 29518281). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, and animal models (PMIDs: 29307555, 29604224, 29604224). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 24, 2021 (SOP Version 7).

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: Ambry Genetics

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 4AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29518281; 29604224

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS13D variants in ClinVar

15 Conditions Cataloged

not providedTotal: 1297

Inborn genetic diseasesTotal: 559

Autosomal recessive cerebellar ataxia-saccadic intrusion syndromeTotal: 94

VPS13D-related disorderTotal: 77

not specifiedTotal: 41

Fetal akinesia deformation sequence 1Total: 2

Leigh syndromeTotal: 2

Arthrogryposis multiplex congenitaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015378.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	392 clinvar	33 clinvar	433
missense	1 clinvar	11 clinvar	925 clinvar	49 clinvar	14 clinvar	1000
nonsense	21 clinvar	13 clinvar	3 clinvar			37
start loss						0
frameshift	15 clinvar	9 clinvar	1 clinvar			25
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar	24 clinvar			32
Total	39	39	961	441	47	1527

Highest pathogenic variant AF is 0.000027280155

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015378.4	RefSeq	NP_056193.2	69	MANE Select
ENST00000620676.6	Ensembl	ENSP00000478104.1	69	MANE Select
NM_018156.4	RefSeq	NP_060626.2	68	Standard
ENST00000011700.10	Ensembl	ENSP00000011700.6	52	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein targeting to vacuole
mitochondrion organization
protein retention in Golgi apparatus
positive regulation of mitophagy

Cellular Component

cell
extrinsic component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358136
Coding exons: 69
Length: 281976
Individuals with no LoFs: 125641
Homozygous LoFs: 0
Heterozygous LoFs: 107
Defined: 125748
p: 0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.50	2029	2.37e+3	0.856	0.000134	28782
Missense (PolyPhen)		683	923.31	0.73973		11470
Synonymous	0.0923	905	909	0.996	0.0000516	8653
Loss of Function	9.80	55	207	0.265	0.0000120	2445

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00080	0.00080	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00060	0.00060	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00042	0.00040	rare
South Asian	0.00033	0.00033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions in promoting mitochondrial clearance by mitochondrial autophagy (mitophagy), also possibly by positively regulating mitochondrial fission (PubMed:29307555). Mitophagy plays an important role in regulating cell health and mitochondrial size and homeostasis (PubMed:29307555). {ECO:0000269|PubMed:29307555}.;
Disease: DISEASE: Note=Variants in VPS13D may be the cause of childhood onset movement disorders, characterized in most cases by developmental delay, axial hypotonia and hyperkinetic movement disorders associated with spastic paraparesis, as well as truncal and appendicular ataxia. {ECO:0000269|PubMed:29518281}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.655
RVIS EVS: -4.23
RVIS percentile EVS: 0.14

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.582

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium