3-46898691-A-G

Variant names:

• chr3-46898691-A-G
• rs121434597
• NM_000316.3:c.668A>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000316.3(PTH1R):​c.668A>G​(p.His223Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004021673: Published functional studies suggest H223R results in a constitutively active receptor that is damaging to normal receptor function (Schipani et al., 1995" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTH1R NM_000316.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.12
• Publications: 51 publications found

Genes affected

PTH1R (HGNC:9608): (parathyroid hormone 1 receptor) The protein encoded by this gene is a member of the G-protein coupled receptor family 2. This protein is a receptor for parathyroid hormone (PTH) and for parathyroid hormone-like hormone (PTHLH). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system. Defects in this receptor are known to be the cause of Jansen's metaphyseal chondrodysplasia (JMC), chondrodysplasia Blomstrand type (BOCD), as well as enchodromatosis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

PTH1R Gene-Disease associations (from GenCC):

• metaphyseal chondrodysplasia, Jansen type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• primary failure of tooth eruption

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• chondrodysplasia Blomstrand type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• Eiken syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000308167 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004021673: Published functional studies suggest H223R results in a constitutively active receptor that is damaging to normal receptor function (Schipani et al., 1995; Shimomura-Kuroki et al., 2017); SCV004292690: Experimental studies have shown that this missense change affects PTH1R function (PMID: 7701349).; SCV005876820: In vitro functional analyses demonstrate constitutive, ligand-independent basal cAMP accumulation and increased agonist binding affinity in COS-7 cells expressing the mutant receptor compared to cells expressing the wild-type receptor (Schipani 1995, Schipani 1996, Schipani 1997). PMID: 7701349. PMID: 8703170. PMID: 9178745.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000316.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 3-46898691-A-G is Pathogenic according to our data. Variant chr3-46898691-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000316.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	NM_000316.3	MANE Select	c.668A>G	p.His223Arg	missense	Exon 9 of 16	NP_000307.1	Q03431
	PTH1R	NM_001184744.1		c.668A>G	p.His223Arg	missense	Exon 8 of 15	NP_001171673.1	Q0VGD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	ENST00000449590.6	TSL:1 MANE Select	c.668A>G	p.His223Arg	missense	Exon 9 of 16	ENSP00000402723.1	Q03431
	PTH1R	ENST00000313049.9	TSL:1	c.668A>G	p.His223Arg	missense	Exon 7 of 14	ENSP00000321999.4	Q03431
	PTH1R	ENST00000430002.6	TSL:1	c.668A>G	p.His223Arg	missense	Exon 8 of 15	ENSP00000413774.2	Q03431

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000657 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Metaphyseal chondrodysplasia, Jansen type (1)
1	-	-	Primary failure of tooth eruption (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.97		Gain of MoRF binding (P = 0.0064)
MVP		0.95
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	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: rs121434597; hg19: chr3-46940181;