rs114368325

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

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 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:16

Conservation

PhyloP100: 1.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-54158135-C-T is described in Lovd as [Pathogenic].

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 [Likely_pathogenic]. Clinvar id is 29679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54158136-G-A is described in Lovd as [Pathogenic]. Variant chr20-54158136-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP24A1	NM_000782.5 linkuse as main transcript	c.1186C>T	p.Arg396Trp	missense_variant	9/12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8 linkuse as main transcript	c.1186C>T	p.Arg396Trp	missense_variant	9/12	1	NM_000782.5	ENSP00000216862	P1	Q07973-1
CYP24A1	ENST00000395955.7 linkuse as main transcript	c.1186C>T	p.Arg396Trp	missense_variant	9/11	1		ENSP00000379285		Q07973-2
CYP24A1	ENST00000395954.3 linkuse as main transcript	c.760C>T	p.Arg254Trp	missense_variant	7/10	1		ENSP00000379284		Q07973-3

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

GnomAD3 exomes

AF:

0.000665

AC:

167

AN:

251228

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135800

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.000901

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152324

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00113

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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 1

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 20, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 21, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 03, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jan 05, 2024	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 -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 05, 2015	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 20, 2024	PS3, PM3_Strong, PM5, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2021	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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, 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP24A1 protein function. Experimental studies have shown that this missense change affects CYP24A1 function (PMID: 21675912). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CYP24A1: PM3:Very Strong, PM5, PM2:Supporting -

Muscle spasm

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 01, 2015

- -

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

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;.

MutationTaster

Benign

1.0

D;D;D

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over