Submissions for variant NM_002734.5(PRKAR1A):c.220C>T (p.Arg74Cys)

gnomAD frequency: 0.00002  dbSNP: rs137853303

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013510	SCV000950751	uncertain significance	Carney complex, type 1	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the PRKAR1A protein (p.Arg74Cys). This variant is present in population databases (rs137853303, gnomAD 0.01%). This missense change has been observed in individual(s) with Carney complex (PMID: 15371594). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12674). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PRKAR1A function (PMID: 15371594, 18241045). 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	2023-04-19	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.
Sema4, Sema4	RCV001014797	SCV002534728	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
GeneDx	RCV003320547	SCV004025847	uncertain significance	not provided	2023-02-14	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; Published functional studies are conflicting: one study demonstrates protein expression levels and protein kinase A (PKA) activity similar to wildtype, while another shows increased PKA activity possibly due to decreased binding of cAMP (Veugelers et al., 2004; Greene et al., 2008); This variant is associated with the following publications: (PMID: 26130139, 23942052, 21111774, 20358582, 15992699, 19650827, 21115159, 29264456, 22112814, 15371594, 18241045, 25637381, 18760947, 16491075)
PreventionGenetics, part of Exact Sciences	RCV003407324	SCV004109155	uncertain significance	PRKAR1A-related disorder	2023-04-18	criteria provided, single submitter	clinical testing	The PRKAR1A c.220C>T variant is predicted to result in the amino acid substitution p.Arg74Cys. This variant was reported to segregate in a family with Carney complex (Figure S5, Veugelers et al. 2004. PubMed ID: 15371594). Functional studies using patient-derived lymphoblastoid cell lines showed that this variant does not significantly alter basal or cAMP-stimulated protein kinase A (PKA) activity (Veugelers et al. 2004. PubMed ID: 15371594). However, a different study showed that this variant leads to decreased binding to cAMP and increased PKA activity (Greene et al. 2008. PubMed ID: 18241045). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-66518939-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003466855	SCV004206511	uncertain significance	Acrodysostosis 1 with or without hormone resistance	2023-12-04	criteria provided, single submitter	clinical testing
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