ClinVar Miner

Submissions for variant NM_000376.3(VDR):c.985G>C (p.Glu329Gln)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV003340994 SCV004047921 uncertain significance Vitamin D-dependent rickets type II with alopecia criteria provided, single submitter clinical testing The c.985G>C (p.Glu329Gln) missense variant in VDR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu329Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Glu at position 329 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu329Gln in VDR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV003340994 SCV005441771 likely pathogenic Vitamin D-dependent rickets type II with alopecia criteria provided, single submitter research A missense variant, c.985G>C in exon 9 of VDR was observed in a homozygous state in the proband. Sanger validation and segregation analysis showed that the variant was present in homozygous state in the proband and in heterozygous state in his parents. The variant is absent in gnomAD (v4.1.0) and our in-house database of 3384 exomes. our in-house database of 3384 exomes. In-silico analysis tools (REVEL, CADD and MutationTaster) predict the variant as disease-causing and likely to affect the VDR function. This variant has been reported as variant of uncertain significance by one submitter in the ClinVar database (ID: 2585094). Another missense variant at the same amino acid position, c.985G>A p.(Glu329Lys) has been reported as pathogenic in compound heterozygous state with a frameshift variant c.366del in association with vitamin D resistant rickets (Miller et al., 2001).

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