Gene Validity Classification Summary

Gene/Disease Pair:

CDC73 : hyperparathyroidism-jaw tumor syndrome

HGNC:16783 | MONDO_0007768
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
Carpten JD et al. 2002 Dec (PMID:12434154);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
1.5
1.5
Carpten JD et al. 2002 Dec (PMID:12434154);
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 1  
Candidate gene sequencing 4.83 3
Carpten JD et al. 2002 Dec (PMID:12434154);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.83    
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 2 2
Gill AJ et al. 2006 Sep (PMID:16931959); Tan MH et al. 2004 Oct 1 (PMID:15475453);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Pazienza V et al. 2013 Dec 5 (PMID:24340015);
Models Non-human model organism 2 0 - 4 4 1 3 3
Walls GV et al. 2017 July 13 (PMID:28288139);
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) 5.5

 


 

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 5.5 17.5 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
10/12/2018
EXPERT CURATION (DATE)
Definitive
10/12/2018
EVIDENCE SUMMARY
There is abundant published evidence associating the CDC73 gene with hyperparathyroidism-jaw tumor syndrome, since the gene-disease relationship was first proposed by Carpten et al. (2002). Multiple case level studies have been performed with HPT-JT patients that have variants in the CDC73 gene. Loss of nuclear expression and immunoreactivity of Parafibromin was reported in Parathyroid Carcinoma of HPT-JT patients. Functional characterization of three mutations from CDC73 patients caused cell overgrowth in cell proliferation assay. CDC73 deficient mice (Both Cdc73+/− mice and the conditional Cdc73+/L/PTH- Cre and Cdc73L/L/PTH-Cre mice) develop parathyroid and uterine tumours. All of these types of evidence are consistent with a definitive relationship between the CDC73 gene and hyperparathyroidism-jaw tumor syndrome.