NM_000376.3:c.1036G>A

Variant names:

• chr12-47844994-C-T
• rs267607169
• NM_000376.3:c.1036G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_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:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.51
• Publications: 9 publications found

Genes affected

VDR (HGNC:12679): (vitamin D receptor) This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

VDR Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0582 (below the threshold of 3.09). Trascript score misZ: 2.1887 (below the threshold of 3.09). GenCC associations: The gene is linked to vitamin D-dependent rickets, type 2A, vitamin D-dependent rickets, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 12-47844994-C-T is Pathogenic according to our data. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844994-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 7759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.1036G>A	p.Val346Met	missense_variant	Exon 10 of 10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.1036G>A	p.Val346Met	missense_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250198 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460492 Hom.: 0 Cov.: 53 AF XY: 0.00000275 AC XY: 2 AN XY: 726632

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia Pathogenic:3

-

FAHD UNIT, Department of Genetics, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Jul 16, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.64
MutPred		0.65		Gain of catalytic residue at P341 (P = 0.0047);Gain of catalytic residue at P341 (P = 0.0047);Gain of catalytic residue at P341 (P = 0.0047);.;
MVP		0.96
MPC		1.1
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.82
gMVP		0.77
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267607169; hg19: chr12-48238777; COSMIC: COSV57468936;