Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000001736 | SCV000380506 | likely pathogenic | Vitamin D-dependent rickets, type 1 | 2017-04-28 | criteria provided, single submitter | clinical testing | The CYP27B1 c.1166G>A (p.Arg389His) missense variant has been reported in at least four studies in which it is found in a compound heterozygous state in five patients with vitamin D-dependent rickets (Wang et al. 1998; Wang et al. 2002; Yan et al. 2011; Durmaz et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in mouse testicular Leydig MA-10 cells revealed the variant resulted in no detectable 1-α-hydroxylase activity (Wang et al. 1998). Three other variants resulting in the abolition of enzyme activity are also found at the Arg389 residue (Sawada et al. 2001). Based on the evidence, the p.Arg389His variant is classified as likely pathogenic for vitamin D-dependent rickets. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Gene |
RCV000481523 | SCV000564924 | pathogenic | not provided | 2023-08-03 | criteria provided, single submitter | clinical testing | Functional studies demonstrate that the R389H variant has no detectable 1-alpha-hydroxylase activity (Wang et al., 1998); 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: 17488797, 22190362, 23483640, 22443290, 24308945, 9837822, 12050193, 18394115, 11737215, 21700898, 31589614) |
| Labcorp Genetics |
RCV000481523 | SCV001578500 | pathogenic | not provided | 2024-10-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the CYP27B1 protein (p.Arg389His). This variant is present in population databases (rs118204009, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive vitamin D-dependent rickets, type I (VDDR1A) (PMID: 9837822, 12050193, 17488797, 18394115, 22443290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1669). Invitae Evidence 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 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 CYP27B1 protein function. Experimental studies have shown that this missense change affects CYP27B1 function (PMID: 9837822). For these reasons, this variant has been classified as Pathogenic. |
| Center for Genomic Medicine, |
RCV000481523 | SCV004027271 | pathogenic | not provided | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV001195099 | SCV005368391 | pathogenic | Vitamin D-dependent rickets, type 1A | 2024-09-18 | criteria provided, single submitter | clinical testing | Criteria applied: PM3_VSTR, PM5_STR, PS3_SUP, PM2_SUP, PP3, PP4; Identified as compund heterozygous with NM_000785.4:c.1427T>C |
| OMIM | RCV001195099 | SCV000021892 | pathogenic | Vitamin D-dependent rickets, type 1A | 2013-03-01 | no assertion criteria provided | literature only |