ClinVar Miner

Submissions for variant NM_024529.5(CDC73):c.842G>A (p.Arg281His)

gnomAD frequency: 0.00001  dbSNP: rs762716583
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001221778 SCV001393840 uncertain significance Parathyroid carcinoma 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 281 of the CDC73 protein (p.Arg281His). This variant is present in population databases (rs762716583, gnomAD 0.0009%). 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: 950136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Genetic Services Laboratory, University of Chicago RCV001819916 SCV002065298 uncertain significance not specified 2021-05-26 criteria provided, single submitter clinical testing DNA sequence analysis of the CDC73 gene demonstrated a sequence change, c.842G>A, in exon 9 that results in an amino acid change, p.Arg281His. This sequence change has been described in the gnomAD database with a frequency of 0.0058% in the African subpopulation (dbSNP rs762716583). The p.Arg281His change affects a moderately conserved amino acid residue located in a domain of the CDC73 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg281His substitution. This sequence change does not appear to have been previously described in patients with CDC73-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg281His change remains unknown at this time.
Sema4, Sema4 RCV002256706 SCV002530572 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-23 criteria provided, single submitter curation
Ambry Genetics RCV002256706 SCV002680719 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-14 criteria provided, single submitter clinical testing The p.R281H variant (also known as c.842G>A), located in coding exon 9 of the CDC73 gene, results from a G to A substitution at nucleotide position 842. The arginine at codon 281 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003462752 SCV004215580 uncertain significance Hyperparathyroidism 1 2023-08-17 criteria provided, single submitter clinical testing

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