rs6068812

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting

The NM_000782.5(CYP24A1):c.1226T>C(p.Leu409Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,914 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.62

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 Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 20-54158096-A-G is Pathogenic according to our data. Variant chr20-54158096-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54158096-A-G is described in Lovd as [Likely_pathogenic]. Variant chr20-54158096-A-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00184 (2696/1461544) while in subpopulation NFE AF= 0.00231 (2571/1111976). AF 95% confidence interval is 0.00224. There are 4 homozygotes in gnomad4_exome. There are 1297 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5 link	c.1226T>C	p.Leu409Ser	missense_variant	Exon 9 of 12	ENST00000216862.8	NP_000773.2	Q07973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP24A1	ENST00000216862.8 link	c.1226T>C	p.Leu409Ser	missense_variant	Exon 9 of 12	1	NM_000782.5	ENSP00000216862.3	Q07973-1
CYP24A1	ENST00000395955.7 link	c.1226T>C	p.Leu409Ser	missense_variant	Exon 9 of 11	1		ENSP00000379285.3	Q07973-2
CYP24A1	ENST00000395954.3 link	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 10	1		ENSP00000379284.3	Q07973-3

Frequencies

GnomAD3 genomes

AF:

0.000788

AC:

120

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000749

AC:

188

AN:

251066

Hom.:

AF XY:

0.000781

AC XY:

106

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00184

AC:

2696

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1297

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00231

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152370

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000858

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.00185

EpiControl

AF:

0.00142

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 1

Pathogenic:7

Jul 08, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2022

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.1226T>C (p.Leu409Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 251066 control chromosomes. This frequency does not allow conclusions about variant significance. c.1226T>C has been reported in the literature in multiple individuals affected with features of Hypercalcemia, Infantile type 1, Hypercalciuric Nephrolithiasis and Nephrocalcinosis, including one case of apparent homozygosity due to UPD(20)mat leading to infantile hypercalcemia (example, Schlingmann_2011, Dinour_2013, Mugg_2015, Hureaux_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Schlingmann_2011 and Mugg_2015). The most pronounced variant effect results in <10-30% of normal CYP24A1 enzyme activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely pathogenic, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 03, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2024

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP24A1: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 409 of the CYP24A1 protein (p.Leu409Ser). This variant is present in population databases (rs6068812, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypercalcemia and/or nephrolithiasis (PMID: 21675912, 23470222, 26214117, 26846157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29680). 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, 23423976). For these reasons, this variant has been classified as Pathogenic. -

Oct 14, 2016

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CYP24A1-related disorder

Pathogenic:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYP24A1 c.1226T>C variant is predicted to result in the amino acid substitution p.Leu409Ser. This variant has been reported as causative in the homozygous and compound heterozygous states in many individuals with autosomal recessive hypercalcaemia (Schlingmann et al. 2011. PubMed ID: 21675912; Mugg et al. 2015. PubMed ID: 25375986; Gahl WA et al 2016. PubMed ID: 26846157; Hanna C et al 2021. PubMed ID: 34307984). Functional studies indicate this variant has only ~32% of wild-type activity (Jacobs ET et al 2013. PubMed ID: 23423976; Mugg et al. 2015. PubMed ID: 25375986). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;T;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.93

MVP

0.97

MPC

0.44

ClinPred

0.10

GERP RS

5.3

Varity_R

0.93

gMVP

0.96

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