Submissions for variant NM_002734.5(PRKAR1A):c.221G>A (p.Arg74His)

gnomAD frequency: 0.00036  dbSNP: rs200069356

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000990054	SCV000287677	likely benign	Carney complex, type 1	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000990054	SCV000405878	likely benign	Carney complex, type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000384218	SCV000405879	likely benign	Acrodysostosis 1 with or without hormone resistance	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Ambry Genetics	RCV000561393	SCV000674431	likely benign	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588205	SCV000698020	likely benign	not specified	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: PRKAR1A c.221G>A (p.Arg74His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251254 control chromosomes (gnomAD). The observed variant frequency is approximately 220 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAR1A causing Carney Complex phenotype (1.9e-06), strongly suggesting that the variant is benign. Although the variant c.221G>A has been reported in the literature in an individual affected with Ovarian cancer (Castellanos 2016), Carney Complex (Tsay 2017), and Pituitary adenomas (de LaPiscina_ 2021). At-least one of these individuals affected with Pituitary adenomas had a pathogenic co-occurrence in AIP gene, c.811C>T;p.R271W (de LaPiscina_ 2021). One of these studies (Tsay 2017), also performed a functional evaluation on the variant of interest, and found that the variant protein was expressed, and while it did not directly alter protein kinase A activity, an increased intracellular level of phosphorylated CREB was observed as a downstream effect; hence indicating an overall increase in cAMP signaling. However, this study does not allow a clearly convincing conclusion about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 28051113, 29264456, 34313605). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=5) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV004701317	SCV001140822	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000990054	SCV002012399	uncertain significance	Carney complex, type 1	2021-09-16	criteria provided, single submitter	clinical testing	The PRKAR1A c.221GA (p.Arg74His) missense change has a maximum frequency of 0.10% in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/17-66518940-G-A). Although this frequency is higher than expected for a pathogenic variant associated with Carney complex (PMID: 20301463), this variant has been reported in an individual with Carney complex whose pituitary tumor demonstrated loss of heterozygosity (PMID: 29264456). It has also been reported in multiple individuals with a clinical presentation not suggestive of Carney complex (PMID: 28051113, 32443704, internal data). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). In silico tools are not in agreement about the effect of this variant on protein function. Functional studies of HEK293 cells transfected with a plasmid containing this variant indicated that this variant caused a modest increase in cAMP signaling (PMID: 20301463). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS1, PP2.
Genetic Services Laboratory, University of Chicago	RCV000588205	SCV002069146	likely benign	not specified	2019-06-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561393	SCV002534729	likely benign	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003947769	SCV004761952	uncertain significance	PRKAR1A-related disorder	2023-12-19	no assertion criteria provided	clinical testing	The PRKAR1A c.221G>A variant is predicted to result in the amino acid substitution p.Arg74His. This variant has been reported in individuals with pituitary adenomas (Table 3, Martínez de LaPiscina et al. 2021. PubMed ID: 34313605; Tsay et al. 2017. PubMed ID: 29264456) and ovarian cancer (Castellanos et al. 2017. PubMed ID: 28051113). It has also been reported in individuals undergoing hereditary cancer testing (Table S1, Velázquez et al. 2020. PubMed ID: 32522261). This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD, which may be too high to be a primary cause of disease and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239382/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.