PYCR1

protein-coding

pyrroline-5-carboxylate reductase 1

Gene summary

This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

MANE transcript

NM_006907.4

Inheritance

ClinVar variants

P:56U:109B:104

Top phenotype

Cutis laxa, autosomal recessive, type IIB; Cutis laxa, autosomal recessive type IIIB

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr17:81,932,384-81,942,412

External References & Databases

Ensembl (ENSG00000183010)

Transcript & Mutation Effects

hg38 • Region Span ~10.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PYCR1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013755

Submitter: Genomics England PanelApp

PYCR1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013755

Submitter: PanelApp Australia

autosomal recessive cutis laxa type 2BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: PanelApp Australia

autosomal recessive cutis laxa type 2BSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: Orphanet

geroderma osteodysplasticumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009271

Submitter: Orphanet

autosomal recessive cutis laxa type 2BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive cutis laxa type 2BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: Genomics England PanelApp

autosomal recessive cutis laxa type 2BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: ClinGen

PYCR1 was first reported in relation to autosomal recessive cutis laxa in 2009 (Guernsey DL, et al., 2009, PMID: 19576563; Reversade B, et al., 2009, PMID: 19648921). At least 40 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 13 probands in the two initial publications. Variants in this gene segregated with disease in two additional family members (Guernsey DL, et al., 2009, PMID: 19576563). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the function of PYCR1 in proline metabolism, its expression in bone and skin, and animal models in Xenopus and Zebrafish with partial recapitulation of disease. In summary, PYCR1 is definitively associated with autosomal recessive cutis laxa. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

PYCR1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013755

Submitter: G2P

PYCR1-related de Barsy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013755

Submitter: Ambry Genetics

autosomal recessive cutis laxa type 2BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013051

Submitter: G2P

Clinical Genomic Database (CGD)

Cutis laxa, autosomal recessive, type IIB; Cutis laxa, autosomal recessive type IIIBAR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; 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: 4076251; 11424136; 16045708; 18304158; 18348262; 19576563; 19401719; 19648921; 21204221; 21567914; 21834030; 22052856

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PYCR1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 298

not specifiedTotal: 47

Autosomal recessive cutis laxa type 2BTotal: 40

Inborn genetic diseasesTotal: 38

Cutis laxaTotal: 35

PYCR1-related disorderTotal: 26

PYCR1-related de Barsy syndromeTotal: 24

Wiedemann-Rautenstrauch-like progeroid syndromeTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006907.4. 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				94 clinvar	2 clinvar	96
missense	3 clinvar	19 clinvar	106 clinvar	7 clinvar	1 clinvar	136
nonsense		4 clinvar	1 clinvar			5
start loss						0
frameshift	9 clinvar	9 clinvar				18
splice donor/acceptor (+/-2bp)	4 clinvar	8 clinvar	2 clinvar			14
Total	16	40	109	101	3	269

Highest pathogenic variant AF is 0.00014014322

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006907.4	RefSeq	NP_008838.2	7	MANE Select
ENST00000329875.13	Ensembl	ENSP00000328858.8	7	MANE Select
NM_001282279.2	RefSeq	NP_001269208.1	6	Standard
NM_001282280.2	RefSeq	NP_001269209.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pycr1b	Danio rerio	Structure: post-vent region Quality: increased curvature abnormal

Gene / Model

Organism

Observed Phenotype

pycr1b

Danio rerio

Structure: post-vent region

Quality: increased curvature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Amino Acid metabolism
Urea cycle and metabolism of amino groups
Metabolism of amino acids and derivatives
Metabolism

Biological Process

proline biosynthetic process
cellular amino acid biosynthetic process
cellular response to oxidative stress
regulation of mitochondrial membrane potential
oxidation-reduction process

Molecular Function

pyrroline-5-carboxylate reductase activity
protein binding
identical protein binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329875
Coding exons: 7
Length: 10029
Individuals with no LoFs: 125475
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125506
p: 0.000124

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.173	187	194	0.965	0.0000130	2039
Missense (PolyPhen)		49	65.038	0.75341		662
Synonymous	0.170	81	83.0	0.976	0.00000613	684
Loss of Function	0.988	7	10.4	0.670	5.54e-7	118

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.00033	0.00033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Housekeeping enzyme that catalyzes the last step in proline biosynthesis. Can utilize both NAD and NADP, but has higher affinity for NAD. Involved in the cellular response to oxidative stress. {ECO:0000269|PubMed:16730026, ECO:0000269|PubMed:19648921}.;
Disease: DISEASE: Cutis laxa, autosomal recessive, 2B (ARCL2B) [MIM:612940]: A disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, a general connective tissue weakness, and varying degrees of growth and developmental delay and neurological abnormalities. Patients do not manifest metabolic abnormalities. {ECO:0000269|PubMed:19576563, ECO:0000269|PubMed:19648921}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cutis laxa, autosomal recessive, 3B (ARCL3B) [MIM:614438]: A disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation, and cutis laxa. {ECO:0000269|PubMed:19648921, ECO:0000269|PubMed:22052856}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.263

Intolerance Scores

LoFtool: 0.449
RVIS EVS: -0.53
RVIS percentile EVS: 20.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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