rs267607169
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000376.3(VDR):c.1036G>A(p.Val346Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000376.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250198Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135348
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460492Hom.: 0 Cov.: 53 AF XY: 0.00000275 AC XY: 2AN XY: 726632
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Vitamin D-dependent rickets type II with alopecia Pathogenic:3
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not provided Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at