PPCS

protein-coding

phosphopantothenoylcysteine synthetase

Gene summary

Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. PPCS (EC 6.3.2.5), one of the last enzymes in this pathway, converts phosphopantothenate to phosphopantothenoylcysteine (Daugherty et al., 2002 [PubMed 11923312]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_024664.4

Inheritance

AR, AD

ClinVar variants

P:3U:126B:115

Top phenotype

Cardiomyopathy, dilated, 2C

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr1:42,456,117-42,473,385

External References & Databases

Ensembl (ENSG00000127125)

Transcript & Mutation Effects

hg38 • Region Span ~17.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathy, dilated, 2cSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032592

Submitter: Labcorp Genetics (formerly Invitae)

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

cardiomyopathy, dilated, 2cMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032592

Submitter: Ambry Genetics

cardiomyopathy, dilated, 2cSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032592

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 2CAR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Individuals have been described as affected by dilated cardiomyopathy, and awareness may allow prompt management (eg, oral pantethine supplementation has been described as beneficial)

Refs: 29754768

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPCS variants in ClinVar

7 Conditions Cataloged

not providedTotal: 243

Inborn genetic diseasesTotal: 35

not specifiedTotal: 17

PPCS-related disorderTotal: 12

Cardiomyopathy, dilated, 2cTotal: 6

Cardiovascular phenotypeTotal: 4

Leukoencephalopathy with vanishing white matter 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024664.4. 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			1 clinvar	105 clinvar	4 clinvar	110
missense	1 clinvar	2 clinvar	107 clinvar	6 clinvar		116
nonsense			7 clinvar			7
start loss			3 clinvar			3
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	2	126	111	4	244

Highest pathogenic variant AF is 6.840516e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024664.4	RefSeq	NP_078940.2	3	MANE Select
ENST00000372561.4	Ensembl	ENSP00000361642.3	3	MANE Select
NM_001077447.3	RefSeq	NP_001070915.1	2	Standard
NM_001287506.1	RefSeq	NP_001274435.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pantothenate and CoA biosynthesis - Homo sapiens (human)
Pantothenate and CoA Biosynthesis
Coenzyme A biosynthesis
Metabolism
Vitamin B5 (pantothenate) metabolism

Biological Process

coenzyme biosynthetic process
coenzyme A biosynthetic process

Molecular Function

phosphopantothenate--cysteine ligase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372561
Coding exons: 3
Length: 17269
Individuals with no LoFs: 124753
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 124797
p: 0.000176

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.802	144	174	0.829	0.00000838	1955
Missense (PolyPhen)		51	66.169	0.77075		742
Synonymous	-1.09	86	74.0	1.16	0.00000376	679
Loss of Function	1.65	5	10.9	0.460	6.29e-7	120

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00064	0.00064	rare
Ashkenazi Jewish	0.00080	0.00079	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0.00083	0.00082	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the first step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'- phosphopantothenate to form 4-phosphopantothenoylcysteine. {ECO:0000269|PubMed:11923312, ECO:0000269|PubMed:12906824}.;

Recessive Scores

pRec: 0.159

Intolerance Scores

LoFtool: 0.300
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.0255

Gene Damage Prediction

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