ClinVar Genomic variation as it relates to human health
NM_000782.5(CYP24A1):c.1226T>C (p.Leu409Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(5); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000782.5(CYP24A1):c.1226T>C (p.Leu409Ser)
Variation ID: 29680 Accession: VCV000029680.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.2 20: 54158096 (GRCh38) [ NCBI UCSC ] 20: 52774635 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Jul 15, 2024 Feb 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000782.5:c.1226T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000773.2:p.Leu409Ser missense NM_001128915.2:c.1226T>C NP_001122387.1:p.Leu409Ser missense NC_000020.11:g.54158096A>G NC_000020.10:g.52774635A>G NG_008334.1:g.20882T>C Q07973:p.Leu409Ser - Protein change
- L409S
- Other names
- CYP24A1, LEU409SER (rs6068812)
- Canonical SPDI
- NC_000020.11:54158095:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00131
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00071
The Genome Aggregation Database (gnomAD), exomes 0.00075
The Genome Aggregation Database (gnomAD) 0.00084
Trans-Omics for Precision Medicine (TOPMed) 0.00086
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
CYP24A1 | - | - |
GRCh38 GRCh37 |
314 | 326 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Apr 20, 2023 | RCV000033210.41 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000785821.28 | |
CYP24A1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 5, 2024 | RCV003894819.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jul 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercalcemia, infantile, 1
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448825.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Language impairment (present) , Speech articulation difficulties (present) , Global developmental delay (present) , Abnormality of the optic nerve (present) , Delayed … (more)
Seizures (present) , Language impairment (present) , Speech articulation difficulties (present) , Global developmental delay (present) , Abnormality of the optic nerve (present) , Delayed speech and language development (present) , Short stature (present) , Chronic diarrhea (present) , Dolichocephaly (present) , Deeply set eye (present) , Frontal bossing (present) , Generalized hypotonia (present) , Small for gestational age (present) , Recurrent hypoglycemia (present) , Episodic fever (present) , Lactic acidosis (present) , Chronic neutropenia (present) , Motor aphasia (present) , Recurrent bacterial skin infections (present) (less)
Sex: male
|
|
Pathogenic
(Nov 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercalcemia, infantile, 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766096.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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. (less)
|
|
Likely pathogenic
(Apr 20, 2023)
|
criteria provided, single submitter
Method: research
|
Hypercalcemia, infantile, 1
Affected status: yes
Allele origin:
maternal
|
Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003919041.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
|
|
Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercalcemia, infantile, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018118.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001209677.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP24A1 protein function. Experimental studies have shown that this missense change affects CYP24A1 function (PMID: 21675912, 23423976). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246621.23
First in ClinVar: May 09, 2020 Last updated: Jul 15, 2024 |
Number of individuals with the variant: 4
|
|
Likely pathogenic
(Oct 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000924393.1
First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Comment on evidence:
profound hypercalcemia in pregnanacy
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercalcemia, infantile, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001300125.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
CYP24A1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004718832.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CYP24A1 c.1226T>C variant is predicted to result in the amino acid substitution p.Leu409Ser. This variant has been reported in the homozygous and compound heterozygous … (more)
The CYP24A1 c.1226T>C variant is predicted to result in the amino acid substitution p.Leu409Ser. This variant has been reported in the homozygous and compound heterozygous state in many individuals to be causative for 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. (less)
|
|
Pathogenic
(Nov 03, 2011)
|
no assertion criteria provided
Method: literature only
|
HYPERCALCEMIA, INFANTILE, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000057056.3
First in ClinVar: Apr 04, 2013 Last updated: May 29, 2016 |
Comment on evidence:
For discussion of the leu409-to-ser (L409S) mutation in the CYP24A1 gene that was found in compound heterozygous state in 2 sibs with infantile hypercalcemia (HCINF1; … (more)
For discussion of the leu409-to-ser (L409S) mutation in the CYP24A1 gene that was found in compound heterozygous state in 2 sibs with infantile hypercalcemia (HCINF1; 143880) by Schlingmann et al. (2011), see 126065.0005. In molecular-modeling simulations, Ji and Shen (2011) found that the L409S mutation weakens the binding of 1,25-dihydroxyvitamin D3 to 24-hydroxylase. (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
When a maternal heterozygous mutation of the CYP24A1 gene leads to infantile hypercalcemia through a maternal uniparental disomy of chromosome 20. | Hureaux M | Molecular cytogenetics | 2021 | PMID: 33952337 |
The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine. | Gahl WA | Molecular genetics and metabolism | 2016 | PMID: 26846157 |
CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait. | Molin A | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26214117 |
Kidney function and influence of sunlight exposure in patients with impaired 24-hydroxylation of vitamin D due to CYP24A1 mutations. | Figueres ML | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2015 | PMID: 25446019 |
Quantitation of CYP24A1 enzymatic activity with a simple two-hybrid system. | Mugg A | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25375986 |
Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis. | Dinour D | The Journal of urology | 2013 | PMID: 23470222 |
CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells. | Jacobs ET | Cancer research | 2013 | PMID: 23423976 |
1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. | Nesterova G | Clinical journal of the American Society of Nephrology : CJASN | 2013 | PMID: 23293122 |
CYP24A1 mutations in idiopathic infantile hypercalcemia. | Ji HF | The New England journal of medicine | 2011 | PMID: 22047571 |
Mutations in CYP24A1 and idiopathic infantile hypercalcemia. | Schlingmann KP | The New England journal of medicine | 2011 | PMID: 21675912 |
Text-mined citations for rs6068812 ...
HelpRecord last updated Jul 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.