rs777676129

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_SupportingPP5_Very_Strong

The NM_000782.5(CYP24A1):c.428_430delAAG(p.Glu143del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,613,766 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

CYP24A1
NM_000782.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.33

Publications

31 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: Likely_pathogenic. The variant received 9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000782.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 20-54172927-CCTT-C is Pathogenic according to our data. Variant chr20-54172927-CCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5 link	c.428_430delAAG	p.Glu143del	disruptive_inframe_deletion	Exon 2 of 12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8 link	c.428_430delAAG	p.Glu143del	disruptive_inframe_deletion	Exon 2 of 12	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000529

AC:

133

AN:

251266

AF XY:

0.000552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000528

AC:

771

AN:

1461554

Hom.:

AF XY:

0.000541

AC XY:

393

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000754

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000630

AC:

701

AN:

1112012

Other (OTH)

AF:

0.000580

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000512

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41462

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000955

Hom.:

Bravo

AF:

0.000718

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 1

Pathogenic:8

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CYP24A1 c.428_430delAAG (p.Glu143del) variant is an in-frame deletion variant that is reported often in the literature. Across 14 studies, the variant was identified in a total of 25 individuals with infantile hypercalcemia, including 12 homozygotes and 13 compound heterozygotes, and in eight unaffected heterozygous family members of affected individuals (Schlingmann et al. 2011; Streeten et al. 2011; Dauber et al. 2012; Nesterova et al. 2013; Dinour et al. 2013; Wolf et al. 2014; Jacobs et al 2014; Dowen et al. 2014; Dinour et al. 2015; Figueres et al. 2015; Shah et al. 2015; Jobst-Schwan et al. 2015; Braun et al. 2016; Gigante et al. 2016). Segregation analysis was compatible with autosomal recessive inheritance. The variant was absent from at least 204 control alleles and is reported at a frequency of 0.00218 in the European American population of the Exome Sequencing Project. Functional studies in V79-4 Chinese hamster lung fibroblast cells showed that the p.Glu143del variant resulted in ablation of CYP24A1 catabolic activity (Schlingmann et al. 2011). Based on the collective evidence, the p.Glu143del 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. -

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region of the CYP24A1 protein, p.(Glu143del). The region deleted is highly conserved (100 vertebrates, UCSC). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.1% (131/129,132 alleles) in the European non-Finnish population. This variant has been reported in multiple individuals with idiopathic infantile hypercalcaemia in the homozygous and compound heterozygous state (PMID: 21675912, 34858904, 34551392, 34307984, 33099630, 34125233 ). The variant has been reported to segregate with idiopathic hypercalcaemia in affected family members (PMID: 21675912). An in vitro functional assay with limited validation showed a complete loss of enzyme activity (PMID: 21675912). 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, PM4_Supporting, PS3_Supporting -

Nov 03, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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, PM4,PP4 -

Jan 11, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2023

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.428_430delAAG (p.Glu143del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00053 in 251266 control chromosomes in the gnomAD database, including 1 homozygotes. c.428_430delAAG has been reported in the literature in multiple individuals affected with infantile hypercalcemia or adult hypercalcemia. 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 and showed that this variant resulted in ablation of CYP24A1 catabolic activity (Schlingmann_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 10, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Sep 03, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on enzyme activity (PMID: 21675912); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 34805638, 34320495, 22047571, 23293122, 23470222, 31842586, 24875559, 25194629, 22047572, 26787776, 27639704, 26846157, 26304832, 26097993, 28324001, 28874334, 26501157, 29786188, 31028937, 31751313, 31980526, 26585929, 22112808, 31089432, 27394135, 21675912, 24518185, 24423361, 34426522, 31589614, 33099630, 33186763, 35569070, 28109821, 33502802, 34307984, 38476635, 37768904, 38665259, 38780860, 38156538, 38544324) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.428_430del, results in the deletion of 1 amino acid(s) of the CYP24A1 protein (p.Glu143del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777676129, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with idiopathic infantile hypercalcemia and hypercalciuric nephrolithiasis (PMID: 21675912, 22047572, 22112808, 23293122, 23470222, 24423361, 24875559, 25194629, 26097993, 26304832, 26787776, 26846157, 27394135, 27639704). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29677). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CYP24A1 function (PMID: 21675912). For these reasons, this variant has been classified as Pathogenic. -

Jul 20, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.3

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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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