Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HMGCS2 : 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

HGNC:5008 | MONDO_0011614
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Fatty Acid Oxidation Disorders 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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 8
15.5
12
Aledo R et al. 2001 Jul (PMID:11479731); Wolf NI et al. 2003 Apr (PMID:12647205); Ramos M et al. 2013 Aug (PMID:23751782); Pitt JJ et al. 2015 May (PMID:25511235);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 7
4.75
Bouchard L et al. 2001 Mar (PMID:11228257); Pitt JJ et al. 2015 May (PMID:25511235); Zschocke J et al. 2002 Jun (PMID:12072887);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Boukaftane Y et al. 1994 Oct (PMID:7851882);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Vilà-Brau A et al. 2011 Jun 10 (PMID:21502324);
Models Non-human model organism 2 0 - 4 4
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) 1

 


 

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 1 13 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
10/11/2018
EXPERT CURATION (DATE)
Definitive
05/22/2018