12-47846374-C-G

Variant names:

• chr12-47846374-C-G
• rs121909802
• NM_000376.3:c.985G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_000376.3(VDR):​c.985G>C​(p.Glu329Gln) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E329K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.07
• 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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47846374-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7748.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, 0.918
• PP5: Variant 12-47846374-C-G is Pathogenic according to our data. Variant chr12-47846374-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2585094.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.985G>C	p.Glu329Gln	missense_variant	Exon 9 of 10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.985G>C	p.Glu329Gln	missense_variant	Exon 9 of 10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia Pathogenic:1 Uncertain:1

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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A missense variant, c.985G>C in exon 9 of VDR was observed in a homozygous state in the proband. Sanger validation and segregation analysis showed that the variant was present in homozygous state in the proband and in heterozygous state in his parents. The variant is absent in gnomAD (v4.1.0) and our in-house database of 3384 exomes. our in-house database of 3384 exomes. In-silico analysis tools (REVEL, CADD and MutationTaster) predict the variant as disease-causing and likely to affect the VDR function. This variant has been reported as variant of uncertain significance by one submitter in the ClinVar database (ID: 2585094). Another missense variant at the same amino acid position, c.985G>A p.(Glu329Lys) has been reported as pathogenic in compound heterozygous state with a frameshift variant c.366del in association with vitamin D resistant rickets (Miller et al., 2001). -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.985G>C (p.Glu329Gln) missense variant in VDR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu329Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Glu at position 329 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu329Gln in VDR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;M;M;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;D
Polyphen		1.0	D;D;D;.
Vest4		0.89
MutPred		0.79		Gain of catalytic residue at E328 (P = 0.0059);Gain of catalytic residue at E328 (P = 0.0059);Gain of catalytic residue at E328 (P = 0.0059);.;
MVP		0.99
MPC		1.2
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.92
gMVP		0.96
Mutation Taster		=27/73	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: rs121909802; hg19: chr12-48240157;