rs114368325

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM5PP3PP5_Very_StrongBS2_Supporting

The NM_000782.5(CYP24A1):c.1186C>T(p.Arg396Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,614,010 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R396Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 3 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 1.72

Publications

60 publications found

Variant links:

Genes affected

CYP24A1 (HGNC:2602): (cytochrome P450 family 24 subfamily A member 1) 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]

CYP24A1 Gene-Disease associations (from GenCC):

hypercalcemia, infantile, 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal recessive infantile hypercalcemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP24A1 links:

ENSG00000286587 (HGNC:):

ENSG00000286587 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-54158135-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 953906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

PP5

Variant 20-54158136-G-A is Pathogenic according to our data. Variant chr20-54158136-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5 link	c.1186C>T	p.Arg396Trp	missense_variant	Exon 9 of 12	ENST00000216862.8	NP_000773.2	Q07973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8 link	c.1186C>T	p.Arg396Trp	missense_variant	Exon 9 of 12	1	NM_000782.5	ENSP00000216862.3		Q07973-1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000665

AC:

167

AN:

251228

AF XY:

0.000655

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00140

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000779

AC:

1138

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000799

AC XY:

581

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00154

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000901

AC:

1002

AN:

1111974

Other (OTH)

AF:

0.000629

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

134

201

268

335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152324

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41558

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000659

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.00107

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 1

Pathogenic:13

May 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 21, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CYP24A1 c.1186C>T (p.Arg396Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00066 in 251228 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CYP24A1 causing Infantile Hypercalcemia 1, allowing no conclusion about variant significance. c.1186C>T has been observed in the homozygous and compound heterozygous state in multiple individuals affected with Idiopathic Infantile Hypercalcemia (e.g. Schlingmann_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found that the variant resulted in a complete loss of enzyme activity (e.g. Schlingmann_2011). The following publication has been ascertained in the context of this evaluation (PMID: 21675912). ClinVar contains an entry for this variant (Variation ID: 29679). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in CYP24A1 is predicted to replace arginine with tryptophan at codon 396, p.(Arg396Trp). The arginine residue is highly conserved (100 vertebrates, UCSC). There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.1% (148/129,106 alleles) in the European non-Finnish population. This variant has been reported in multiple individuals with idiopathic infantile hypercalcaemia in the homozygous or compound heterozygous state (PMID: 21675912, 24518185, 23001465, 36703897, 34858904, 37701149). An in vitro functional assay with limited validation demonstrated the variant leads to a complete loss of enzyme activity (PMID: 21675912). A knock-in mouse model for the variant demonstrated a decrease in vitamin D levels and an increase in calcium levels indicating that this variant impacts protein function due to its reduced enzyme activity (PMID: 21675912, 35956396). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.873). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3, PS3_Moderate -

Oct 20, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CYP24A1 c.1186C>T (p.Arg396Trp) variant has been reported in seven studies and identified in a total of ten individuals with infantile hypercalcemia including three homozygotes and seven compound heterozygotes, two of which are siblings (Schlingmann et al. 2011; Fencl et al. 2013; Skalova et al. 2013; Dinour et al. 2015; Cools et al. 2015; Shah et al. 2015; Figueres et al. 2015). The p.Arg396Trp variant was identified in four of 1024 control alleles and is reported at a frequency of 0.001482 in the European (Finnish) population of the Genome Aggregation Database. Schlingmann et al. (2011) performed functional studies using transiently transfected V79-4 cells and observed a complete loss of enzyme activity in cells with the variant protein as compared to wild type. Based on the collective evidence, the p.Arg396Trp variant is classified as pathogenic for infantile hypercalcemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 05, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

This patient is a carrier of a heterozygous pathogenic variant in the CYP24A1 gene implicated in causing autosomal recessive infantile hypercalcemia (MIM 143880). The CYP24A1 variant (c.1186C>T) was identified in several patients in both the homozygous and compound heterozygous state (Schlingmann et al. 2011, PMID: 21675912; Fencl et al. 2013, PMID: 23001465; Wolf et al. 2014, PMID: 24518185). Functional studies of this variant showed an inability of the protein to metabolize 1,25-dihydroxyvitamin D3 (Schlingmann et al. 2011, PMID: 21675912). -

Feb 17, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 20, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM3_Strong, PM5, PP3 -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG: PS1, PS3, PP3, PP4 -

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:6

Jan 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate this variant results in the loss of enzymatic activity (PMID: 21675912); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26097993, 36703897, 37701149, 23485543, 34337279, 34805638, 34320495, 34515170, 32743688, 35325889, 23001465, 24518185, 22047571, 25194629, 21675912, 26117226, 28324001, 30729229, 29786188, 27798933, 31751313, 3490596, 25446019, 27394135, 31672324, 31980526, 26585929, 34307984, 34426522, 31589614, 33099630, 33186763, 33226606, 33502802, 33726816, 35569070, 28470390) -

Oct 17, 2014

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 396 of the CYP24A1 protein (p.Arg396Trp). This variant is present in population databases (rs114368325, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with idiopathic infantile hypercalcemia (PMID: 21675912, 23001465, 23485543, 25446019, 27394135, 27798933, 28470390). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29679). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP24A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP24A1 function (PMID: 21675912). For these reasons, this variant has been classified as Pathogenic. -

Feb 07, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP24A1: PM3:Very Strong, PM5, PM2:Supporting -

Inborn genetic diseases

Pathogenic:1

Mar 05, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1186C>T (p.R396W) alteration is located in exon 9 (coding exon 9) of the CYP24A1 gene. This alteration results from a C to T substitution at nucleotide position 1186, causing the arginine (R) at amino acid position 396 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.07% (199/282630) total alleles studied. The highest observed frequency was 0.148% (37/24972) of European (Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other CYP24A1 variants in individuals with features consistent with CYP24A1-related infantile hypercalcemia; in at least one instance, the variants were identified in trans (Leszczynska, 2024; Collins, 2023; Brancatella, 2022; Brunerova, 2022; Hanna, 2021; De Bonis, 2021; Pronicka, 2017; Gigante, 2016; Shah, 2015; Fencl, 2013; Schlingmann, 2011). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Muscle spasm

Pathogenic:1

Jul 01, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.5

H;H;.

PhyloP100

1.7

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.96

MVP

0.96

MPC

0.39

ClinPred

0.20

GERP RS

2.0

Varity_R

0.95

gMVP

0.92

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over