20-54172927-CCTT-C
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000782.5(CYP24A1):c.428_430del(p.Glu143del) variant causes a 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 inframe_deletion
NM_000782.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.33
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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 id is 29677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54172927-CCTT-C is described in Lovd as [Likely_pathogenic]. Variant chr20-54172927-CCTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CYP24A1 | NM_000782.5 | c.428_430del | p.Glu143del | inframe_deletion | 2/12 | ENST00000216862.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP24A1 | ENST00000216862.8 | c.428_430del | p.Glu143del | inframe_deletion | 2/12 | 1 | NM_000782.5 | P1 | |
| CYP24A1 | ENST00000395955.7 | c.428_430del | p.Glu143del | inframe_deletion | 2/11 | 1 | |||
| CYP24A1 | ENST00000472970.1 | n.265_267del | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes 0.000512 AC: 78AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000529 AC: 133AN: 251266Hom.: 1 AF XY: 0.000552 AC XY: 75AN XY: 135836
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GnomAD4 exome AF: 0.000528 AC: 771AN: 1461554Hom.: 1 AF XY: 0.000541 AC XY: 393AN XY: 727088
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GnomAD4 genome 0.000512 AC: 78AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 33AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercalcemia, infantile, 1 Pathogenic:6
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 03, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jan 05, 2024 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 23, 2023 | 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. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | 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 protein 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2023 | Published functional studies demonstrate a damaging effect on enzyme activity (Schlingmann KP et al., 2011); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34805638, 34320495, 22047571, 23293122, 23470222, 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jul 20, 2021 | - - |
Computational scores
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