Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000522189 | SCV000617570 | uncertain significance | not provided | 2017-06-30 | criteria provided, single submitter | clinical testing | The R73Q variant in the VDR gene has been reported previously, in the homozygous state, in two Haitian sisters with hypocalcemic vitamin D resistant rickets, however no other genes were evaluated (Hughes et al., 1988). The R73Q variant is observed in 1/16512 (0.0061%) alleles from individuals of South Asian background, but no homozygous individuals were reported, in the ExAC dataset (Lek et al., 2016). The R73Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the nuclear receptor DNA biding domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R73Q as a variant of uncertain significance. |
Labcorp Genetics |
RCV000522189 | SCV002126820 | likely pathogenic | not provided | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 73 of the VDR protein (p.Arg73Gln). This variant is present in population databases (rs121909791, gnomAD 0.02%). This missense change has been observed in individuals with vitamin D-dependent rickets (PMID: 2849209, 28620554). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg70 to Gln. ClinVar contains an entry for this variant (Variation ID: 7746). 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 VDR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects VDR function (PMID: 2849209). 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. |
Mendelics | RCV000008187 | SCV002519951 | pathogenic | Vitamin D-dependent rickets type II with alopecia | 2022-05-04 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000008187 | SCV000028394 | pathogenic | Vitamin D-dependent rickets type II with alopecia | 1988-12-23 | no assertion criteria provided | literature only |