Submissions for variant NM_024529.5(CDC73):c.844A>G (p.Thr282Ala)

gnomAD frequency: 0.00002  dbSNP: rs201236330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533137	SCV000636209	uncertain significance	Parathyroid carcinoma	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 282 of the CDC73 protein (p.Thr282Ala). This variant is present in population databases (rs201236330, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. ClinVar contains an entry for this variant (Variation ID: 462770). 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 not expected to disrupt CDC73 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002413493	SCV002675997	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The p.T282A variant (also known as c.844A>G), located in coding exon 9 of the CDC73 gene, results from an A to G substitution at nucleotide position 844. The threonine at codon 282 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002476135	SCV002786759	uncertain significance	Hyperparathyroidism 1; Parathyroid carcinoma; Hyperparathyroidism 2 with jaw tumors	2021-10-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003441927	SCV004170801	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15632063, 15923622)
Baylor Genetics	RCV004568798	SCV005060044	uncertain significance	Hyperparathyroidism 1	2023-12-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732938	SCV005359474	uncertain significance	CDC73-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The CDC73 c.844A>G variant is predicted to result in the amino acid substitution p.Thr282Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/462770/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.