rs121434597

Positions:

• chr3-46898691-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTH1R NM_000316.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• 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 id is 13742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46898691-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH1R	NM_000316.3	c.668A>G	p.His223Arg	missense_variant	9/16	ENST00000449590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH1R	ENST00000449590.6	c.668A>G	p.His223Arg	missense_variant	9/16	1	NM_000316.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 223 of the PTH1R protein (p.His223Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Jansen-type metaphyseal chondrodysplasia (PMID: 7701349, 22278430). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13742). 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 PTH1R protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTH1R function (PMID: 7701349). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7701349, 2716029, 31977144, 8076140, 20489161, 27160269, 22278430, 8703170, 30975883, 27410178, 31430259, 31693237) -

Metaphyseal chondrodysplasia, Jansen type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 05, 1996

- -

Primary failure of tooth eruption Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;D;D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.3	H;H;.;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.0	D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99	D;D;.;D;D
Vest4		0.97
MutPred		0.97		Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);Gain of MoRF binding (P = 0.0064);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434597; hg19: chr3-46940181;