chr12-47846743-C-G

Variant names:

• chr12-47846743-C-G
• rs121909796
• NM_000376.3:c.821G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000376.3(VDR):​c.821G>C​(p.Arg274Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47846743-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7752.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.935

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.821G>C	p.Arg274Pro	missense	Exon 8 of 10	NP_000367.1
	VDR	NM_001364085.2		c.821G>C	p.Arg274Pro	missense	Exon 8 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.971G>C	p.Arg324Pro	missense	Exon 8 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.821G>C	p.Arg274Pro	missense	Exon 8 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.971G>C	p.Arg324Pro	missense	Exon 8 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.821G>C	p.Arg274Pro	missense	Exon 6 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg274 amino acid residue in VDR. Other variant(s) that disrupt this residue have been observed in individuals with VDR-related conditions (PMID: 8392085, 22145479, 28620554), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 274 of the VDR protein (p.Arg274Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VDR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1504399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VDR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.74		Gain of catalytic residue at L273 (P = 0)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs121909796; hg19: chr12-48240526;