Submissions for variant NM_000376.3(VDR):c.1036G>A (p.Val346Met)

dbSNP: rs267607169

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001818143	SCV002069217	likely pathogenic	not provided	2018-07-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VDR gene demonstrated a sequence change, c.1036G>A, in exon 11 that results in an amino acid change, p.Val346Met. This particular amino acid change has been described in the homozygous state in three affected family members with hereditary vitamin D-resistant rickets (HVDRR) (Arita et. al., 2008). In vitro functional assays demonstrated impaired transcriptional activity, and impaired ligand binding affinity for this variant (Tamura et. al., 2017). This sequence change has been described in the gnomAD database with a low population frequency of 0.0004% (dbSNP rs267607169). The p.Val346Met change affects a highly conserved amino acid residue located in a domain of the VDR protein that is known to be functional. The p.Val346Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change is the likely cause of the indicated phenotype, however functional studies have not been performed to prove this conclusively.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000008200	SCV004805602	likely pathogenic	Vitamin D-dependent rickets type II with alopecia	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000008200	SCV000028407	pathogenic	Vitamin D-dependent rickets type II with alopecia	2008-01-01	no assertion criteria provided	literature only
FAHD UNIT, Department of Genetics, King Faisal Specialist Hospital and Research Centre	RCV000008200	SCV005043358	likely pathogenic	Vitamin D-dependent rickets type II with alopecia		no assertion criteria provided	clinical testing