Gene Validity Classification Summary

Gene/Disease Pair:

RET : Hereditary pheochromocytoma-paraganglioma

HGNC:9967 | OrphaNet: 29072 | OMIM:164761
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
5.0
5
Smith DP et al. 1997 Sep 4 (PMID:9294615); Castellone MD et al. 2010 Oct (PMID:20039896); Tessitore A et al. 1999 Oct (PMID:10522989);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7.0 7
Fishbein L et al. 2017 Feb 13 (PMID:28162975); Mulligan LM et al. 1993 Jun 3 (PMID:8099202); Eng C et al. 1995 Dec (PMID:8825918); Eng C et al. 1996 Nov 20 (PMID:8918855); Neumann HP et al. 2002 May 9 (PMID:12000816);
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 Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7
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
Aggregate Variant Analysis 0-6 12
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 2.0 2
Fishbein L et al. 2017 Feb 13 (PMID:28162975); Tessitore A et al. 1999 Oct (PMID:10522989); Burnichon N et al. 2011 Oct 15 (PMID:21784903);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Carlomagno F et al. 1997 Feb 1 (PMID:9012462); Santoro M et al. 1995 Jan 20 (PMID:7824936);
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 2.0 2
Smith-Hicks CL et al. 2000 Feb 15 (PMID:10675330);
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) 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)*
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
06/16/2017
EXPERT CURATION (DATE)
DEFINITIVE
06/16/2017
Assertion made by the Hereditary Cancer Working Group. Definitive association with pheochromocytoma as a part of Multiple Endocrine neoplasia 2 (MEN 2) syndrome.