CYP24A1

protein-coding

cytochrome P450 family 24 subfamily A member 1, the group of Cytochrome P450 family 24

Gene summary

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein initiates the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D3, by hydroxylation of the side chain. In regulating the level of vitamin D3, this enzyme plays a role in calcium homeostasis and the vitamin D endocrine system. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP24

MANE transcript

NM_000782.5

Inheritance

ClinVar variants

P:73U:176B:67

Top phenotype

Hypercalcemia, infantile 1

gnomAD constraint

pLI —, LoF o/e 1.15

Max pathogenic AF

—

Genomic locus

chr20:54,153,446-54,173,986

External References & Databases

Ensembl (ENSG00000019186)

Transcript & Mutation Effects

hg38 • Region Span ~20.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercalcemia, infantile, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020739

Submitter: Labcorp Genetics (formerly Invitae)

hypercalcemia, infantile, 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020739

Submitter: ClinGen

The *CYP24A1* gene is located on chromosome 20 at q13.2 and encodes the mitochondrial 1,25-dihydroxyvitamin D(3) 24-hydroxylase protein. This protein plays a key role in vitamin D/calcium metabolism and homeostasis through initiating inactivation of calcitriol (physiologically active vitamin D3 - 1,25-dihydroxyvitamin D3) and inactivation of vitamin D precursor calcidiol (25-hydroxyvitamin D3). Gene expression is mainly in the proximal tubules of the kidney cortex and medulla. *CYP24A1* was first reported in relation to autosomal recessive infantile hypercalcemia, type 1 in 2011 (Schlingmann et al., PMID: 21675912). The mechanism of pathogenicity is known to be loss-of-function. The condition can be diagnosed from infancy through to adulthood with key clinical features that include hypercalcemia, hypercalciuria and suppressed intact parathyroid hormone level. Biochemically, elevated calcidiol levels and/or calcitriol and/or abnormal Vitamin D metabolite ratios can be detected. Vitamin D supplementation is a known trigger. At least 19 variants (8 missense, 1 in-frame indel, 3 nonsense, 6 frameshift, 1 canonical splice site) have been reported in 15 probands in 5 publications (PMIDs: 21675912, 25446019, 25194629, 26214117, 28470390) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by animal models. Homozygous Cyp24a1 knockout and Cyp24a1 R396W mutant mice had impaired Vitamin D catabolism and calcium homeostasis recapitulating the human phenotype (PMIDs: 35956396, 10875271). A total of 4/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CYP24A1* and autosomal recessive infantile hypercalcemia type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date October 20th, 2022 (SOP Version 9).

hypercalcemia, infantile, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020739

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive infantile hypercalcemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007749

Submitter: Orphanet

hypercalcemia, infantile, 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020739

Submitter: G2P

Clinical Genomic Database (CGD)

Hypercalcemia, infantile 1AR

Manifestation: Endocrine; Renal

Intervention: Endocrine; Renal

Rationale: Individuals may present early in life with typical hypercalcemic signs/symptoms (eg, failure to thrive,dehydration, and muscular hypotonia or lethargy), or may present later with nephrolithiasis and nephrocalcinosis, and dietary measures, including avoidance of certain vitamin supplements (eg, vitamin D-containing compounds) to avoid hypercalcemia can be beneficial

Refs: 3490596; 21675912; 22047572; 23293122

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP24A1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 203

Hypercalcemia, infantile, 1Total: 196

Inborn genetic diseasesTotal: 70

CYP24A1-related disorderTotal: 29

not specifiedTotal: 17

CYP24A1-related disordersTotal: 12

Renal tubulopathiesTotal: 5

Muscle spasmTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000782.5. 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			4 clinvar	40 clinvar	2 clinvar	46
missense	1 clinvar	16 clinvar	165 clinvar	22 clinvar	3 clinvar	207
nonsense	9 clinvar	14 clinvar	3 clinvar			26
start loss		1 clinvar				1
frameshift	14 clinvar	8 clinvar				22
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	4 clinvar			14
Total	28	45	176	62	5	316

Highest pathogenic variant AF is 0.0017448266

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000782.5	RefSeq	NP_000773.2	11	MANE Select
ENST00000216862.8	Ensembl	ENSP00000216862.3	11	MANE Select
NM_001128915.2	RefSeq	NP_001122387.1	10	Standard
NM_001424340.1	RefSeq	NP_001411269.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid biosynthesis - Homo sapiens (human)
MicroRNAs in cancer - Homo sapiens (human)
Vitamin D Metabolism
Vitamin D Receptor Pathway
Nuclear Receptors in Lipid Metabolism and Toxicity

Biological Process

osteoblast differentiation
vitamin metabolic process
response to vitamin D
vitamin D metabolic process
vitamin D catabolic process

Molecular Function

iron ion binding
25-hydroxycholecalciferol-24-hydroxylase activity
oxidoreductase activity
heme binding
1-alpha,25-dihydroxyvitamin D3 24-hydroxylase activity

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial outer membrane
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216862
Coding exons: 11
Length: 20525
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 120
Defined: 125748
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.10	332	280	1.19	0.0000156	3345
Missense (PolyPhen)		145	121.48	1.1936		1411
Synonymous	-0.969	123	110	1.12	0.00000608	973
Loss of Function	-0.729	32	27.9	1.15	0.00000138	329

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0015	0.0015	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.00026	0.00026	rare
Other	0.00083	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has a role in maintaining calcium homeostasis. Catalyzes the adrenodoxin-dependent 24-hydroxylation of calcidiol (25- hydroxyvitamin D(3)) and calcitriol (1-alpha,25-dihydroxyvitamin D(3)). The enzyme can perform up to 6 rounds of hydroxylation of calcitriol leading to calcitroic acid. It also shows 23- hydroxylating activity leading to 1-alpha,25-dihydroxyvitamin D(3)-26,23-lactone as end product. {ECO:0000269|PubMed:15574355}.;
Disease: DISEASE: Hypercalcemia, infantile, 1 (HCINF1) [MIM:143880]: A disorder characterized by abnormally high level of calcium in the blood, failure to thrive, vomiting, dehydration, and nephrocalcinosis. {ECO:0000269|PubMed:21675912}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.424

Intolerance Scores

LoFtool: 0.973
RVIS EVS: 0.02
RVIS percentile EVS: 55.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.219

Gene Damage Prediction

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