Submissions for variant NM_000782.5(CYP24A1):c.425AAG[1] (p.Glu143del)

dbSNP: rs777676129

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000022527	SCV000434445	pathogenic	Hypercalcemia, infantile, 1	2017-04-27	criteria provided, single submitter	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.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000785819	SCV000924391	uncertain significance	not provided	2015-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV000785819	SCV001390437	pathogenic	not provided	2024-01-19	criteria provided, single submitter	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 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.
Revvity Omics, Revvity	RCV000022527	SCV002024012	pathogenic	Hypercalcemia, infantile, 1	2023-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000785819	SCV002538747	pathogenic	not provided	2023-04-29	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022527	SCV003845143	pathogenic	Hypercalcemia, infantile, 1	2023-02-23	criteria provided, single submitter	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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000022527	SCV004045922	pathogenic	Hypercalcemia, infantile, 1	2023-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000022527	SCV000043816	pathogenic	Hypercalcemia, infantile, 1	2011-11-03	no assertion criteria provided	literature only