rs114368325

chr20-54158136-G-Achr20-54158136-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5 PP3 PP5_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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: CYP24A1 NM_000782.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.72

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]

ACMG classification

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 ClinVar as [Likely_pathogenic]. Clinvar id 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 [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	UniProt
CYP24A1	NM_000782.5	c.1186C>T	p.Arg396Trp	missense_variant	9/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8	c.1186C>T	p.Arg396Trp	missense_variant	9/12	1	NM_000782.5	P1
CYP24A1	ENST00000395955.7	c.1186C>T	p.Arg396Trp	missense_variant	9/11	1
CYP24A1	ENST00000395954.3	c.760C>T	p.Arg254Trp	missense_variant	7/10	1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152206 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.000655 AC XY: 89 AN XY: 135800

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.: 3 Cov.: 32 AF XY: 0.000799 AC XY: 581 AN XY: 727158

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.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74482

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.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercalcemia, infantile, 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -
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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 21, 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. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2021	- -
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, no assertion criteria provided	literature only	OMIM	Nov 03, 2011	- -

not provided Pathogenic:5

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	Invitae	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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CYP24A1: PM3:Very Strong, PM5, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	Published functional studies demonstrate this variant results in the loss of enzymatic activity (Schlingmann et al., 2011); 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, 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) -

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	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.5	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
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	T
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

Other links and lift over

dbSNP: rs114368325; hg19: chr20-52774675; COSMIC: COSV53775287; COSMIC: COSV53775287;