Submissions for variant NM_000316.3(PTH1R):c.1586A>G (p.Asn529Ser)

gnomAD frequency: 0.00004  dbSNP: rs199740724

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000396389	SCV000444803	uncertain significance	Chondrodysplasia Blomstrand type	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000315099	SCV000444804	uncertain significance	Metaphyseal chondrodysplasia, Jansen type	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000734476	SCV000862622	uncertain significance	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000734476	SCV002137238	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 529 of the PTH1R protein (p.Asn529Ser). This variant is present in population databases (rs199740724, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PTH1R-related conditions. ClinVar contains an entry for this variant (Variation ID: 345599). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002487519	SCV002786751	uncertain significance	Primary failure of tooth eruption; Chondrodysplasia Blomstrand type; Eiken syndrome; Metaphyseal chondrodysplasia, Jansen type	2022-04-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523262	SCV003539723	uncertain significance	Inborn genetic diseases	2021-12-16	criteria provided, single submitter	clinical testing	The c.1586A>G (p.N529S) alteration is located in exon 16 (coding exon 14) of the PTH1R gene. This alteration results from a A to G substitution at nucleotide position 1586, causing the asparagine (N) at amino acid position 529 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004745354	SCV005361406	uncertain significance	PTH1R-related disorder	2024-04-28	no assertion criteria provided	clinical testing	The PTH1R c.1586A>G variant is predicted to result in the amino acid substitution p.Asn529Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.