Gene Validity Classification Summary

Gene/Disease Pair:

PRKG1 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:9414 | OrphaNet: 91387 | OMIM:176894
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.0
0
Proband with predicted or proven null variant 1.5 0-2 10 0.0 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7.5 7
Guo DC et al. 2013 Aug 8 (PMID:23910461); Gago-Díaz M et al. 2016 Sep (PMID:27442293); ( PMID 23910461: Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. Also the GOF property of this mutation was demonstrated by functional assays. Proband score=4 *1.5=6 PMID 27442293: One proband with the Arg177Gln mutation ,segregating in 7 affected and 5 unaffected members. Points=1 *1.5 )
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 7.0 7
Guo DC et al. 2013 Aug 8 (PMID:23910461); (PMID 23910461: PRKG1 c.530G>A (p.Arg177Gln) segregated with aortic disease in these families with a combined two-point LOD score of 7.88. )
2 4
1.5 3
1 1.5
   
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 1.0 1
Guo DC et al. 2013 Aug 8 (PMID:23910461); (Biochemical function: Regulation of control of VSMC relaxation via phosphorylation of myosin regulatory light chain. Similar to disease mechanisms from MYLK, MYH11, ACTA2 mutations known to cause disease. Points=0.5 Protein Interaction: Physical interaction with myosin (phosphorylation via regulation of phosphatase). Regulation of smooth muscle contractile apparatus similar to MYLK, a gene strongly associated with thoracic aortic aneurysm (TAA) and aortic dissection. Points=0.5)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Guo DC et al. 2013 Aug 8 (PMID:23910461); (Patient cells: Reduced phosphorylated myosin regulatory light chain in patient fibroblasts compared with controls. Points 1 Non patient cells: Transfection of HEK cells with mutations in PRKG1 increases cGMP-controlled kinase activity suggesting gain of function property. Points=1)
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 1.5 1.5
Pfeifer A et al. 1998 Jun 1 (PMID:9606187); (PRKG1-k/o mice: PRKG1 k/o showed reduced responsiveness of aortic rings to acetylcholine – reduced relaxation PRKG1 k/o were hypertensive. Mouse model: 1pts (abnormalities of aortic function but no TAA phenotype) Clear abnormal aortic phenotype but not directly mimicking human disease - 1 point. )
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

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 4.5 16.5 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
CALCULATED CLASSIFICATION (DATE)
STRONG
07/12/2016
EXPERT CURATION (DATE)
STRONG
12/22/2016
Assertion made by the Aortopathy working group. One point subtracted for weak mouse model phenotype (does not recapitulate gain of function) .