12-57763666-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000785.4(CYP27B1):​c.1358G>A​(p.Arg453His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CYP27B1
NM_000785.4 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B 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. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 12-57763666-C-T is Pathogenic according to our data. Variant chr12-57763666-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 267276.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP27B1NM_000785.4 linkuse as main transcriptc.1358G>A p.Arg453His missense_variant 8/9 ENST00000228606.9 NP_000776.1 O15528

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP27B1ENST00000228606.9 linkuse as main transcriptc.1358G>A p.Arg453His missense_variant 8/91 NM_000785.4 ENSP00000228606.4 O15528
CYP27B1ENST00000547344.5 linkuse as main transcriptn.1497G>A non_coding_transcript_exon_variant 7/82

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
151924
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000968
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251352
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.0000289
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461880
Hom.:
0
Cov.:
36
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000629
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
151924
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74188
show subpopulations
Gnomad4 AFR
AF:
0.0000968
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000511
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 453 of the CYP27B1 protein (p.Arg453His). This variant is present in population databases (rs759208930, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of vitamin D-dependent rickets (PMID: 20926527, 36321535). ClinVar contains an entry for this variant (Variation ID: 267276). 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) performed at Invitae indicates that this missense variant is expected to disrupt CYP27B1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg453 amino acid residue in CYP27B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
CYP27B1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 28, 2022The CYP27B1 c.1358G>A variant is predicted to result in the amino acid substitution p.Arg453His. This variant has been reported along with a second pathogenic CYP27B1 variant in one individual with Pseudovitamin D-deficiency rickets (Supplemental Table 1, Edouard et al 2011. PubMed ID: 20926527). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-58157449-C-T). A different variant affecting the same amino acid (p.Arg459Cys) has also been reported in association with Pseudovitamin D-deficiency rickets (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). In summary, this variant is interpreted as likely pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 23, 2023Variant summary: CYP27B1 c.1358G>A (p.Arg453His) 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 2.4e-05 in 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1358G>A has been reported in the literature in an individual affected with Vitamin D-dependent rickets (Edouard_2011). Although, other changes to this amino acid (R453L and R453C) have been classified as likely pathogenic in ClinVar, the available evidence is currently insufficient to determine the role of this variant in disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.71
D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.98
MVP
0.94
MPC
1.5
ClinPred
0.98
D
GERP RS
5.1
Varity_R
0.93
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs759208930; hg19: chr12-58157449; COSMIC: COSV105849026; COSMIC: COSV105849026; API