rs777676129

chr20-54172927-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: CYP24A1 NM_000782.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 29677.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=7}. 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 AF: 0.000512 AC: 78 AN: 152212 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000529 AC: 133 AN: 251266 Hom.: 1 AF XY: 0.000552 AC XY: 75 AN XY: 135836

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 SAS exome AF: 0.0000980

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.: 1 AF XY: 0.000541 AC XY: 393 AN XY: 727088

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000754

Gnomad4 NFE exome AF: 0.000630

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 33 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercalcemia, infantile, 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2023	- -
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	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:2 Uncertain:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Feb 27, 2015	- -
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) -

Computational scores

Source: dbNSFP v4.3

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: rs777676129; hg19: chr20-52789466;