PDSS2

protein-coding

decaprenyl diphosphate synthase subunit 2

Gene summary

The protein encoded by this gene is an enzyme that synthesizes the prenyl side-chain of coenzyme Q, or ubiquinone, one of the key elements in the respiratory chain. The gene product catalyzes the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. Defects in this gene are a cause of coenzyme Q10 deficiency.[provided by RefSeq, Oct 2009]

Previous symbols:

C6orf210

MANE transcript

NM_020381.4

Inheritance

ClinVar variants

P:9U:130B:80

Top phenotype

Coenzyme Q10 deficiency 3

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr6:107,152,562-107,459,564

External References & Databases

Ensembl (ENSG00000164494)

Transcript & Mutation Effects

hg38 • Region Span ~307.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

coenzyme Q10 deficiency, primary, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013838

Submitter: Labcorp Genetics (formerly Invitae)

coenzyme Q10 deficiency, primary, 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013838

Submitter: G2P

coenzyme Q10 deficiency, primary, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013838

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PDSS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The PDSS2 gene encodes prenyl diphosphate synthase subunit 2, which is important early in the coenzyme Q10 biosynthesis pathway. Coenzyme Q10 is critical for many processes in the cell, including in the mitochondrial respiratory chain transferring electrons from complexes I and II to complex III. The PDSS2 gene was first reported in association with autosomal recessive Leigh syndrome spectrum in 2006 (PMID: 17186472). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants identified in one cases from one publications (PMID: 17186472), as well as a case reported in a book chapter (Quinzii C, Loos M. Multisystemic Infantile CoQ10 Deficiency with Renal Involvement. In: Russell P. Saneto, Sumit Parikh and Bruce H. Cohen, editors. Mitochondrial Case Studies Underlying Mechanisms and Diagnosis. Academic Press; 2016. pp 299-04). 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, expression, functional alteration in patient cells, functional alteration in non-patient cells, and animal models (PMIDs: 27977873, 21139605, 17186472, 29967258, 18437205, 23150520). In summary, there is moderate 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 July 13, 2020 (SOP Version 7).

Clinical Genomic Database (CGD)

Coenzyme Q10 deficiency 3AR

Manifestation: Biochemical; Neurologic; Renal

Intervention: Biochemical

Rationale: Treatment with Coenzyme Q10 supplementation may be beneficial

Refs: 17186472; 22231380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDSS2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 213

Coenzyme Q10 deficiency, primary, 3Total: 60

Inborn genetic diseasesTotal: 44

not specifiedTotal: 37

PDSS2-related disorderTotal: 14

Kidney disorderTotal: 5

Focal segmental glomerulosclerosisTotal: 2

Nephrotic syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020381.4. 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			2 clinvar	70 clinvar		72
missense		3 clinvar	117 clinvar	8 clinvar	2 clinvar	130
nonsense		1 clinvar	4 clinvar			5
start loss			1 clinvar			1
frameshift		3 clinvar	3 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	3 clinvar			5
Total	1	8	130	78	2	219

Highest pathogenic variant AF is 0.000076221404

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020381.4	RefSeq	NP_065114.3	8	MANE Select
ENST00000369037.9	Ensembl	ENSP00000358033.4	8	MANE Select
ENST00000369031.4	Ensembl	ENSP00000358027.4	4	Standard
ENST00000369031.5	Ensembl	ENSP00000358027.4	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Terpenoid backbone biosynthesis - Homo sapiens (human)
Metabolism
Ubiquinol biosynthesis
Metabolism of cofactors
Metabolism of vitamins and cofactors

Biological Process

ubiquinone biosynthetic process
isoprenoid biosynthetic process
regulation of body fluid levels
protein heterotetramerization

Molecular Function

trans-hexaprenyltranstransferase activity
protein heterodimerization activity
trans-octaprenyltranstransferase activity

Cellular Component

mitochondrial matrix
cytosol
transferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369037
Coding exons: 8
Length: 307008
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.474	196	216	0.909	0.0000100	2603
Missense (PolyPhen)		50	72.473	0.68992		871
Synonymous	0.813	74	83.4	0.887	0.00000400	789
Loss of Function	1.12	14	19.3	0.724	8.59e-7	234

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Supplies decaprenyl diphosphate, the precursor for the side chain of the isoprenoid quinones ubiquinone-10. {ECO:0000269|PubMed:16262699}.;
Disease: DISEASE: Coenzyme Q10 deficiency, primary, 3 (COQ10D3) [MIM:614652]: A fatal encephalomyopathic form of coenzyme Q10 deficiency with nephrotic syndrome. Coenzyme Q10 deficiency is an autosomal recessive disorder with variable manifestations consistent with 5 major phenotypes. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form. {ECO:0000269|PubMed:17186472}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.742
RVIS EVS: -0.07
RVIS percentile EVS: 48.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.0635

Gene Damage Prediction

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