11-14885847-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4

The NM_001377214.1(CYP2R1):​c.-50T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CYP2R1
NM_001377214.1 5_prime_UTR_premature_start_codon_gain

Scores

10
6
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
CYP2R1 (HGNC:20580): (cytochrome P450 family 2 subfamily R 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 enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into the active ligand for the vitamin D receptor. A mutation in this gene has been associated with selective 25-hydroxyvitamin D deficiency. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 11-14885847-A-G is Pathogenic according to our data. Variant chr11-14885847-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-14885847-A-G is described in Lovd as [Pathogenic]. Variant chr11-14885847-A-G is described in Lovd as [Likely_benign].
BP4
Computational evidence support a benign effect (MetaRNN=0.09614125). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP2R1NM_024514.5 linkuse as main transcriptc.296T>C p.Leu99Pro missense_variant 2/5 ENST00000334636.10 NP_078790.2 Q6VVX0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP2R1ENST00000334636.10 linkuse as main transcriptc.296T>C p.Leu99Pro missense_variant 2/51 NM_024514.5 ENSP00000334592.5 Q6VVX0
CYP2R1ENST00000532805.1 linkuse as main transcriptn.6T>C non_coding_transcript_exon_variant 1/45 ENSP00000465097.1 E9PS56

Frequencies

GnomAD3 genomes
AF:
0.00103
AC:
157
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00371
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000243
AC:
61
AN:
251224
Hom.:
0
AF XY:
0.000133
AC XY:
18
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.00345
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000105
AC:
154
AN:
1461372
Hom.:
0
Cov.:
31
AF XY:
0.0000935
AC XY:
68
AN XY:
726972
show subpopulations
Gnomad4 AFR exome
AF:
0.00394
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.00103
AC:
157
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.000980
AC XY:
73
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00370
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000161
Hom.:
0
Bravo
AF:
0.00119
ESP6500AA
AF:
0.00455
AC:
20
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000346
AC:
42

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Vitamin D hydroxylation-deficient rickets, type 1B Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 18, 2004- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsApr 09, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 13, 2023Variant 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. -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxAug 17, 2022Published 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) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This 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. -
CYP2R1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 06, 2024The 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. -
Vitamin D-dependent rickets, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 08, 2024The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.096
T
MetaSVM
Uncertain
0.73
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.98
MVP
0.95
MPC
0.82
ClinPred
0.26
T
GERP RS
6.2
Varity_R
0.99
gMVP
0.97

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61495246; hg19: chr11-14907393; API