Submissions for variant NM_002734.5(PRKAR1A):c.546G>A (p.Thr182=)

gnomAD frequency: 0.00004  dbSNP: rs117639566

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229573	SCV000287681	likely benign	Carney complex, type 1	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000229573	SCV000405884	benign	Carney complex, type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000404114	SCV000405885	benign	Acrodysostosis 1 with or without hormone resistance	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV000573601	SCV000674433	likely benign	Hereditary cancer-predisposing syndrome	2017-03-07	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.
GeneDx	RCV001697581	SCV000715898	likely benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12641630)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610412	SCV000920084	benign	not specified	2018-03-05	criteria provided, single submitter	clinical testing	Variant summary: PRKAR1A c.546G>A alters a conserved nucleotide resulting in a synonymous change and 5/5 in silico tools predict no significant effect on splicing. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 9.8e-05 in 245944 control chromosomes (gnomAD). The observed variant frequency is approximately 52 fold above 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. To our knowledge, no occurrence of c.546G>A in individuals affected with Carney Complex and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000573601	SCV002534737	likely benign	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV001697581	SCV005211808	likely benign	not provided		criteria provided, single submitter	not provided