ClinVar Miner

Submissions for variant NM_212472.2(PRKAR1A):c.221G>A (p.Arg74His) (rs200069356)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000990054 SCV000287677 likely benign Carney complex, type 1 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing The p.R74H variant (also known as c.221G>A), located in coding exon 2 of the PRKAR1A gene, results from a G to A substitution at nucleotide position 221. The arginine at codon 74 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an individual with Carney complex whose pituitary tumor showed loss of heterozygosity (Tsay CJ et al. J Endocr Soc. 2017 Oct;1:1312-1321). This alteration was also identified from a 122-gene NGS panel in a proband with ovarian cancer at 35 years whose family met Amsterdam criteria; authors state the proband was negative for Lynch syndrome gene mutations (Castellanos E et al. Sci Rep. 2017 Jan;7:39348). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588205 SCV000698020 likely benign not specified 2021-05-10 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. The observed variant frequency is approximately 221 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) and in a patient affected with Carney Complex (Tsay 2017), these reports do not provide unequivocal conclusions about association of the variant with Carney Complex. 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000990054 SCV001140822 uncertain significance Carney complex, type 1 2019-05-28 criteria provided, single submitter clinical testing

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