Submissions for variant NM_000316.3(PTH1R):c.299G>A (p.Gly100Asp)

gnomAD frequency: 0.00218  dbSNP: rs41290646

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000327085	SCV000444767	likely benign	Chondrodysplasia Blomstrand type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000362244	SCV000444768	likely benign	Metaphyseal chondrodysplasia, Jansen type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514382	SCV000610506	likely benign	not provided	2017-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV000514382	SCV001117380	benign	not provided	2024-01-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514382	SCV001472089	likely benign	not provided	2020-12-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001357210	SCV002071033	likely benign	not specified	2018-10-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278547	SCV002566977	likely benign	Connective tissue disorder	2020-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357210	SCV001552602	benign	not specified		no assertion criteria provided	clinical testing	The PTH1R p.Gly100Asp variant was identified in 1 of 168 proband chromosomes (frequency: 0.00595) from individuals with Ollier disease and was present in 1 of 444 control chromosomes (frequency: 0.00225) from healthy individuals (Couvineau_2008_PMID:18559376). The variant was identified in dbSNP (ID: rs41290646), LOVD 3.0 and ClinVar (classified as likely benign by Illumina and Center for Pediatric Genomic Medicine, and as benign by Invitae). The variant was identified in control databases in 563 of 282480 chromosomes (2 homozygous) at a frequency of 0.001993 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 471 of 128948 chromosomes (freq: 0.003653), Other in 15 of 7214 chromosomes (freq: 0.002079), European (Finnish) in 29 of 25098 chromosomes (freq: 0.001155), Latino in 38 of 35402 chromosomes (freq: 0.001073), Ashkenazi Jewish in 3 of 10362 chromosomes (freq: 0.00029), African in 5 of 24916 chromosomes (freq: 0.000201) and South Asian in 2 of 30598 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Gly100 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional in vitro assays demonstrated that the p.Gly100Asp variant results in <5% ligand binding compared to wildtype, however localization and receptor function was not affected by the variant, suggesting no functional effect (Couvineau_2008_PMID:18559376). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.