Submissions for variant NM_000376.3(VDR):c.1027C>T (p.Arg343Cys)

dbSNP: rs1057521095

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421461	SCV000521052	likely pathogenic	not provided	2018-08-28	criteria provided, single submitter	clinical testing	The R343C variant in the VDR gene has been previously reported as a homozygous in one Egyptian individual with vitamin D-resistant rickets (Mazen et al., 2014). This individual's parents were confirmed to be heterozygous, and this variant was not present in 200 control chromosomes of Egyptian origin (Mazen et al., 2014). Additionally, R343C was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R343C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the R343C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689734	SCV005186145	likely pathogenic	Vitamin D-dependent rickets type II with alopecia	2024-05-01	criteria provided, single submitter	clinical testing	Variant summary: VDR c.1027C>T (p.Arg343Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence in exon 11, three nucleotides from the intron 10/exon 11 splice acceptor site. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249704 control chromosomes. c.1027C>T has been reported in the literature in homozygous individuals affected with Vitamin D-Dependent Rickets Type II (e.g. Mazen_2014, Thakur_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24859502, 30967742). ClinVar contains an entry for this variant (Variation ID: 381603). Based on the evidence outlined above, the variant was classified as likely pathogenic.