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
Consequence
NM_000785.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP27B1 | NM_000785.4 | c.1358G>A | p.Arg453His | missense_variant | 8/9 | ENST00000228606.9 | NP_000776.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP27B1 | ENST00000228606.9 | c.1358G>A | p.Arg453His | missense_variant | 8/9 | 1 | NM_000785.4 | ENSP00000228606.4 | ||
CYP27B1 | ENST00000547344.5 | n.1497G>A | non_coding_transcript_exon_variant | 7/8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 151924Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251352Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461880Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6AN XY: 727242
GnomAD4 genome AF: 0.0000592 AC: 9AN: 151924Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74188
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This 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 submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 28, 2022 | The 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 submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2023 | Variant 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at