ClinVar Miner

Submissions for variant NM_212472.2(PRKAR1A):c.220C>T (p.Arg74Cys) (rs137853303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000013510 SCV000950751 uncertain significance Carney complex, type 1 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 74 of the PRKAR1A protein (p.Arg74Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Carney complex in a family (PMID: 15371594). ClinVar contains an entry for this variant (Variation ID: 12674). Experimental studies have reported conflicting results for this missense change. One study indicates that this variant does not affect R1-alpha protein levels and PKA activity (PMID: 15371594) and another has shown that it results in an increase of PKA activity and decrease binding to cAMP (PMID: 18241045). The clinical significance of these findings is uncertain. 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 RCV001014797 SCV001175555 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing The p.R74C variant (also known as c.220C>T), located in coding exon 2 of the PRKAR1A gene, results from a C to T substitution at nucleotide position 220. The arginine at codon 74 is replaced by cysteine, an amino acid with highly dissimilar properties. The p.R74C variant was first reported in an English proband with clinical features of Carney complex such as cardiac myxoma, lentiginosis, breast myxofibroma, thyroid adenoma, pulmonic stenosis, and deafness. Functional studies were also performed to measure basal as well as cAMP-stimulated protein kinase A (PKA) activity in lymphoblasts from this proband and in an in vitro luciferase-reporter assay. Results demonstrated activity levels for this variant were not significantly different than those for wild type PRKAR1A (Veugelers M et al. Proc. Natl. Acad. Sci. U.S.A., 2004 Sep;101:14222-7). In another functional study, this variant was reported to be associated with increased PKA activity and increased PKA-specific activation in assays performed in vitro. Furthermore, the PRKAR1A RIα regulatory subunit, which harbors p.R74C, demonstrated reduced binding with both cAMP and the PRKAR1A Cα catalytic subunit (Greene EL et al. Hum. Mutat., 2008 May;29:633-9). This variant was also identified in an exome cohort, but the clinical history of the proband was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). Based on an internal structural assessment, this alteration results in loss of a predicted phosphorylation motif ([RK]..[ST]) that may be necessary for the functionally confirmed phosphorylation of Ser77 (Han YS et al. Arch. Biochem. Biophys., 2013 Oct;538:25-33). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM RCV000013510 SCV000033757 pathogenic Carney complex, type 1 2008-05-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148738 SCV000190474 uncertain significance Carney complex 2014-06-01 no assertion criteria provided research

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