VCV000002134.20 - ClinVar

NM_024514.5(CYP2R1):c.296T>C (p.Leu99Pro)

Germline

Classification

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.

(7)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024514.5(CYP2R1):c.296T>C (p.Leu99Pro)

Variation ID: 2134 Accession: VCV000002134.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.2 11: 14885847 (GRCh38) [ NCBI UCSC ] 11: 14907393 (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	Apr 4, 2013	Oct 8, 2024	Jan 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024514.5:c.296T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078790.2:p.Leu99Pro	missense
NM_001377214.1:c.-50T>C		5 prime UTR
NM_001377215.1:c.-50T>C		5 prime UTR
NM_001377216.1:c.-50T>C		5 prime UTR
NM_001377217.1:c.134T>C	NP_001364146.1:p.Leu45Pro	missense
NM_001377227.1:c.-50T>C		5 prime UTR
NC_000011.10:g.14885847A>G
NC_000011.9:g.14907393A>G
NG_007936.1:g.11359T>C
	Q6VVX0:p.Leu99Pro

... more HGVS ... less HGVS

Protein change

L99P, L45P

Other names

Canonical SPDI

NC_000011.10:14885846:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00140 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00024

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD) 0.00107

Trans-Omics for Precision Medicine (TOPMed) 0.00119

1000 Genomes Project 0.00140

1000 Genomes Project 30x 0.00172

Links

ClinGen: CA115362 UniProtKB: Q6VVX0#VAR_021534 OMIM: 608713.0001 dbSNP: rs61495246 VarSome

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
Gene	OMIM	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.
CYP2R1		-	-	GRCh38 GRCh37	1	173
PDE3B		-	-	GRCh38 GRCh37	78	253

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.
Vitamin D hydroxylation-deficient rickets, type 1B	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 13, 2023	RCV000002216.7
Vitamin D-dependent rickets, type 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV001195424.5
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV001371299.9
CYP2R1-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 6, 2024	RCV004754234.1

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.
Pathogenic (Jan 13, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Vitamin D hydroxylation-deficient rickets, type 1B Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003801190.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 15128933‚ 28548312‚ 25942481 Comment: Variant summary: CYP2R1 c.296T>C (p.Leu99Pro) 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: CYP2R1 c.296T>C (p.Leu99Pro) 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 0.00024 in 251224 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database. c.296T>C has been reported in the literature in multiple individuals affected with Vitamin D Hydroxylation-Deficient Rickets, Type 1B and has been shown to segregate in multiple families (Cheng_2004, Thacher_2015, Molin_2017). These data indicate that the variant is very likely to be associated with disease. In vitro studies have shown the variant to abolish enzyme activity (Cheng_2004, Thacher_2015, Molin_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Apr 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitamin D hydroxylation-deficient rickets, type 1B Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003834869.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001567857.4 First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 15128933‚ 25942481‚ 28548312 Comment: This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the CYP2R1 protein (p.Leu99Pro). … (more) This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the CYP2R1 protein (p.Leu99Pro). This variant is present in population databases (rs61495246, gnomAD 0.4%). This missense change has been observed in individuals with rickets (PMID: 15128933, 25942481, 28548312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2134). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP2R1 function (PMID: 15128933, 25942481). For these reasons, this variant has been classified as Pathogenic. (less)
Likely Pathogenic (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitamin D-dependent rickets, type 1 Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001365775.2 First in ClinVar: Jul 04, 2020 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 28548312‚ 16549493‚ 25942481‚ 15128933‚ 32115644 Comment: The p.Leu99Pro variant in CYP2R1 has been reported in the homozygous state in 3 individuals (2 Nigerian and 1 Moroccan) with vitamin D-dependent rickets due … (more) The p.Leu99Pro variant in CYP2R1 has been reported in the homozygous state in 3 individuals (2 Nigerian and 1 Moroccan) with vitamin D-dependent rickets due to a disorder in vitamin D metabolism (Cheng 2004 PMID: 15128933, Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312). One of these individuals belonged to a consanguineous family from at least 2 successive generations (Molin 2017 PMID: 28548312). The p.Leu99Pro variant also segregated with disease in 7 affected relatives from 2 families, 5 of whom were from the consanguineous family (Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312). This variant has also been reported in the heterozygous state in one family with vitamin D-dependent rickets, where it segregated with disease in 2 affected relatives (Thacher 2015 PMID: 25942481). Affected heterozygotes in this family had milder symptoms suggesting that while vitamin D-dependent rickets is primarily an autosomal recessive disease, it has characteristics of semi dominant inheritance in this family. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 2134) and has been identified in 0.37% (154/41454) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Its increased frequency suggests that this may be a founder variant in this population, where the prevalence of rickets is relatively higher (Harris 2006 PMID: 16549493). In vitro functional studies provide some evidence that this variant impacts protein function (Cheng 2004 PMID: 15128933, Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312, Casella 2020 PMID: 32115644) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive vitamin D-dependent rickets. ACMG/AMP Criteria applied: PP1_Moderate, PS3_Moderate, PM3, PP3. (less)
Likely pathogenic (Aug 17, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002567383.2 First in ClinVar: Aug 29, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate absent enzyme activity (Cheng et al., 2004; Thacher et al., 2015); In silico analysis supports that this missense variant has a … (more) Published functional studies demonstrate absent enzyme activity (Cheng et al., 2004; Thacher et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34944511, 35739987, 25942481, 15128933, 22855339, 25003556, 15465040, 18511070, 24497297, 23548573, 8201479, 10969262, 32344004, 31841498, 30777056, 32430692, 33715104, 32596195, 27473561, 28716760, 34199067, 28548312, 32115644, 31589614, 33626316, 35973571, 34137732) (less)
Pathogenic (May 18, 2004)	no assertion criteria provided Method: literature only	VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1B Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022374.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 23, 2020	Publications: PubMed (5) PubMed: 8201479‚ 15128933‚ 10969262‚ 25942481‚ 28548312 Comment on evidence: In a young man from Nigeria with rickets due to a defect in vitamin D 25-hydroxylation (VDDR1B; 600081), who was first reported by Casella et … (more) In a young man from Nigeria with rickets due to a defect in vitamin D 25-hydroxylation (VDDR1B; 600081), who was first reported by Casella et al. (1994), Cheng et al. (2004) identified a homozygous T-to-C transition in exon 2 of the CYP2R1 gene, resulting in a leu99-to-pro (L99P) mutation. Cheng et al. (2004) noted that the scarcity of cases of 25-hydroxylase deficiency may reflect genetic polymorphisms that allow alternate pathways to function in some individuals. It may be significant that the patient studied by Cheng et al. (2004) was Nigerian. Individuals with dark skin require exposure to sunlight for longer periods of time to generate requisite levels of vitamin D3 as compared with those of less skin pigmentation and thus may be more sensitive to impaired synthesis of the vitamin. Furthermore, Cheng et al. (2004) sequenced exon 2 of the CYP2R1 gene in 50 control subjects from Nigeria, and identified 1 individual who was heterozygous for the L99P mutation. This result suggests that there may be a founder gene effect in Nigeria, a country in which the prevalence of rickets is high (Thacher et al., 2000). Thacher et al. (2015) identified the L99P missense mutation in 9 patients (3 with homozygosity and 6 with heterozygosity) in 2 generations of 2 Nigerian families with vitamin D hydroxylation-deficient rickets type 1B (VDDR1B; 600081). Patients with homozygosity had lower levels of 25-hydroxyvitamin D than those who were heterozygous, although all were below the normal range. The L99P mutation was in linkage disequilibrium with a consistent haplotype, which was not seen in 10 other affected families, suggesting that these 2 apparently unrelated Nigerian families shared a common origin of the L99P allele. This variant was absent from 59 unrelated subjects of Nigerian origin and 628 unrelated individuals in the 1000 Genomes Project database. In vitro studies showed that the L99P mutation resulted in complete loss of 25-hydroxylase activity. Heterozygous patients had more mild phenotypes than homozygous patients. Oral administration of vitamin D led to negligible increases in serum 25-hydroxyvitamin D in homozygous cases, and significantly lower increases in serum 25-hydroxyvitamin D among heterozygous cases than among controls. The authors concluded that CYP2R1 is the principal 25-hydroxylase in humans. They noted that CYP2R1 alleles have dosage-dependent effects on vitamin D homeostasis, supporting semidominant inheritance. In affected members of a Moroccan family with VDDR1B, Molin et al. (2017) identified homozygosity for the L99P mutation in the CYP2R1 gene. The mutation segregated with the disorder in the family. (less)
Pathogenic (Mar 06, 2024)	no assertion criteria provided Method: clinical testing	CYP2R1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362204.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CYP2R1 c.296T>C variant is predicted to result in the amino acid substitution p.Leu99Pro. This variant has been reported in the homozygous state in at … (more) The CYP2R1 c.296T>C variant is predicted to result in the amino acid substitution p.Leu99Pro. This variant has been reported in the homozygous state in at least three families with Rickets (Cheng et al. 2004. PubMed ID: 15128933; Thacher et al. 2015. PubMed ID: 25942481; Molin et al. 2017. PubMed ID: 28548312). Additionally, functional studies indicate the p.Leu99Pro variant leads to the loss of vitamin D 25-hydroxylase enzyme activity (Cheng et al. 2004. PubMed ID: 15128933; Thacher et al. 2015. PubMed ID: 25942481). Based on the available evidence, we consider the CYP2R1 c.296T>C (p.Leu99Pro) variant to be pathogenic. (less)

Comment:

Variant summary: CYP2R1 c.296T>C (p.Leu99Pro) 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 0.00024 in 251224 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database. c.296T>C has been reported in the literature in multiple individuals affected with Vitamin D Hydroxylation-Deficient Rickets, Type 1B and has been shown to segregate in multiple families (Cheng_2004, Thacher_2015, Molin_2017). These data indicate that the variant is very likely to be associated with disease. In vitro studies have shown the variant to abolish enzyme activity (Cheng_2004, Thacher_2015, Molin_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the CYP2R1 protein (p.Leu99Pro). This variant is present in population databases (rs61495246, gnomAD 0.4%). This missense change has been observed in individuals with rickets (PMID: 15128933, 25942481, 28548312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2134). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP2R1 function (PMID: 15128933, 25942481). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Leu99Pro variant in CYP2R1 has been reported in the homozygous state in 3 individuals (2 Nigerian and 1 Moroccan) with vitamin D-dependent rickets due to a disorder in vitamin D metabolism (Cheng 2004 PMID: 15128933, Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312). One of these individuals belonged to a consanguineous family from at least 2 successive generations (Molin 2017 PMID: 28548312). The p.Leu99Pro variant also segregated with disease in 7 affected relatives from 2 families, 5 of whom were from the consanguineous family (Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312). This variant has also been reported in the heterozygous state in one family with vitamin D-dependent rickets, where it segregated with disease in 2 affected relatives (Thacher 2015 PMID: 25942481). Affected heterozygotes in this family had milder symptoms suggesting that while vitamin D-dependent rickets is primarily an autosomal recessive disease, it has characteristics of semi dominant inheritance in this family. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 2134) and has been identified in 0.37% (154/41454) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Its increased frequency suggests that this may be a founder variant in this population, where the prevalence of rickets is relatively higher (Harris 2006 PMID: 16549493). In vitro functional studies provide some evidence that this variant impacts protein function (Cheng 2004 PMID: 15128933, Thacher 2015 PMID: 25942481, Molin 2017 PMID: 28548312, Casella 2020 PMID: 32115644) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive vitamin D-dependent rickets. ACMG/AMP Criteria applied: PP1_Moderate, PS3_Moderate, PM3, PP3.

Comment:

Published functional studies demonstrate absent enzyme activity (Cheng et al., 2004; Thacher et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34944511, 35739987, 25942481, 15128933, 22855339, 25003556, 15465040, 18511070, 24497297, 23548573, 8201479, 10969262, 32344004, 31841498, 30777056, 32430692, 33715104, 32596195, 27473561, 28716760, 34199067, 28548312, 32115644, 31589614, 33626316, 35973571, 34137732)

Comment:

The CYP2R1 c.296T>C variant is predicted to result in the amino acid substitution p.Leu99Pro. This variant has been reported in the homozygous state in at least three families with Rickets (Cheng et al. 2004. PubMed ID: 15128933; Thacher et al. 2015. PubMed ID: 25942481; Molin et al. 2017. PubMed ID: 28548312). Additionally, functional studies indicate the p.Leu99Pro variant leads to the loss of vitamin D 25-hydroxylase enzyme activity (Cheng et al. 2004. PubMed ID: 15128933; Thacher et al. 2015. PubMed ID: 25942481). Based on the available evidence, we consider the CYP2R1 c.296T>C (p.Leu99Pro) variant to be pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Differential Frequency of CYP2R1 Variants Across Populations Reveals Pathway Selection for Vitamin D Homeostasis.	Casella A	The Journal of clinical endocrinology and metabolism	2020	PMID: 32115644
Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?	Molin A	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2017	PMID: 28548312
CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.	Thacher TD	The Journal of clinical endocrinology and metabolism	2015	PMID: 25942481
Vitamin D and African Americans.	Harris SS	The Journal of nutrition	2006	PMID: 16549493
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.	Cheng JB	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 15128933
Case-control study of factors associated with nutritional rickets in Nigerian children.	Thacher TD	The Journal of pediatrics	2000	PMID: 10969262
A possible genetic defect in 25-hydroxylation as a cause of rickets.	Casella SJ	The Journal of pediatrics	1994	PMID: 8201479

Text-mined citations for rs61495246 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_024514.5(CYP2R1):c.296T>C (p.Leu99Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61495246 ...