Gene Validity Classification Summary

Gene/Disease Pair:

PRKAR1A : Carney complex, type 1

HGNC:9388 | MONDO_0008057
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 7 11 10
Kirschner LS et al. 2000 Sep (PMID:10973256); Casey M et al. 2000 Sep (PMID:10974026);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Veugelers M et al. 2004 Sep 28 (PMID:15371594);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.13 3
Kirschner LS et al. 2000 Sep (PMID:10973256); Veugelers M et al. 2004 Sep 28 (PMID:15371594);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.13    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 2
Kirschner LS et al. 2000 Sep (PMID:10973256); Casey M et al. 2000 Sep (PMID:10974026); Veugelers M et al. 2004 Sep 28 (PMID:15371594);
Functional Alteration Patient cells 1 0 - 2 2 1
1.5
1.5
Kirschner LS et al. 2000 Sep (PMID:10973256);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Veugelers M et al. 2004 Sep 28 (PMID:15371594); Griffin KJ et al. 2004 Dec (PMID:15591278);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
10/09/2018
EXPERT CURATION (DATE)
Definitive
12/21/2018
EVIDENCE SUMMARY
There is abundant evidence published associating the PRKAR1A gene with Carney complex, type 1, since the gene-disease relationship was first proposed by Kirschner et al. (2000). Multiple case level studies have been performed with CNC patients that have variants in the PRKAR1A gene. Western-blot analysis of primary cell lines from multiple patients indicate that nonsense and frameshift mutations led to NMD. prkar1a +/− mice exhibited extracardiac tumorigenesis, developed sarcomas and hepatocellular carcinomas as well as thyroid, adrenocortical and mesenchymal tumors, which sharing similar phenotypes to CNC patients. In patient cells from three families, both the stimulation of kinase activity with cAMP and the inhibition of that stimulation by PKI were greater in CNC tumours than in those in the control samples. All of these types of evidence are consistent with a definitive relationship between the PRKAR1A gene and Carney complex, type 1.