ClinVar Miner

Submissions for variant NM_000316.3(PTH1R):c.668A>G (p.His223Arg)

dbSNP: rs121434597
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV002247338 SCV002518945 pathogenic Primary failure of tooth eruption 2022-05-04 criteria provided, single submitter clinical testing
GeneDx RCV003317036 SCV004021673 pathogenic not provided 2023-07-24 criteria provided, single submitter clinical testing 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV003317036 SCV004292690 pathogenic not provided 2024-01-15 criteria provided, single submitter clinical testing 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.
OMIM RCV000014749 SCV000035004 pathogenic Metaphyseal chondrodysplasia, Jansen type 1996-09-05 no assertion criteria provided literature only

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