Gene Validity Curation

GCDH - glutaryl-CoA dehydrogenase deficiency

Gene: GCDH (HGNC:4189)
Classification - 11/08/2019
Disease: glutaryl-CoA dehydrogenase deficiency (MONDO_0009281)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy
Evidence Summary: The relationship between GCDH and glutaryl CoA dehydrogenase deficiency was evaluated using the ClinGen Clinical Validity Framework as of October 22, 2019. GCDH encodes glutaryl CoA dehydrogenase, a mitochondrial matrix enzyme composed of four identical subunits. This enzyme catalyzes the oxidative decarboxylation of glutaryl-CoA - an intermediate in the metabolism of lysine, hydroxylysine and tryptophan - to crotonyl-CoA and carbon dioxide. Deficiency of GCDH activity causes glutaric acidemia type 1 (GA-1), an autosomal recessive disorder. GA-1 is characterized by macrocephaly, acute encephalopathic crises and progressive movement disorders caused by striatal degeneration, typically with onset between the ages of 6-18 months, and often triggered by an intercurrent infection. Affected individuals present with elevated levels of glutaric acid, 3-hydroxy-glutaric acid, glutaconic acid and glutarylcarnitine and be classified as high excreters or low excreters based on the urine glutaric acid level (Larson and Goodman, 2019, PMID 31536184). Biallelic variants in GCDH were first reported in 1995 (Greenberg et al, PMID 7795610; Goodman et al, PMID 8541831). Since then, around 200 variants have been identified in GCDH. Data from 9 probands who are homozygous or compound heterozygous for GCDH variants were curated, including 9 unique variants (missense, nonsense, frameshift, splicing) (Greenberg et al, 1995, PMID 7795610; Goodman et al, 1995, PMID 8541831; Anikster et al, 1996, PMID 8900228; Moseilhy et al, 2017, PMID 27476540; Zayed et al, 2019, PMID 31062211). One of these variants, c.91+5G>T, segregates in multiple closely related kindreds of an Ojibway-speaking genetic isolate of native Americans living in the Island Lake region of northern Manitoba and nearby communities of northwestern Ontario. (Greenberg et al, 1995, PMID 7795610). An inframe deletion with a dominant-negative impact has also been reported (PMID 22231382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of GCDH which is consistent with the biochemical abnormalities observed in individuals with GCDH deficiency (PMIDs 8287562, 8541831); functional studies (Bross et al, 2012, PMID 22231382; Ribeiro et al, 2019, PMID 31491587), the biochemical and clinical features of a Gcdh knock out mouse (Koeller et al, 2002, PMID 11854167; Zinnanti et al, 2006, PMID 16446282) and biochemical findings in the Egyptian fruit-eating bat which has GCDH deficiency in liver and kidney (McMillan et al, 1998, PMID 3182847). In summary, GCDH is definitively associated with glutaryl CoA dehydrogenase deficiency (GA-1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
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 6
12
12
Anikster Y et al. 1996 Nov (PMID:8900228); Zayed H et al. 2019 Aug (PMID:31062211); Moseilhy A et al. 2017 Feb (PMID:27476540);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3
Goodman SI et al. 1995 Sep (PMID:8541831); Greenberg CR et al. 1995 Mar (PMID:7795610); Anikster Y et al. 1996 Nov (PMID:8900228);
Segregation Evidence   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.78 2
Greenberg CR et al. 1995 Mar (PMID:7795610); Anikster Y et al. 1996 Nov (PMID:8900228);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.78    
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
2
2
Goodman SI et al. 1995 Sep (PMID:8541831); Christensen E et al. 1993 Oct 29 (PMID:8287562);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Ribeiro JV et al. 2019 Sep 3 (PMID:31491587); Bross P et al. 2012 Sep (PMID:22231382);
Models Non-human model organism 2 0 - 4 4 3 3.5 3.5
Koeller DM et al. 2002 Feb 15 (PMID:11854167); Zinnanti WJ et al. 2006 Apr (PMID:16446282); McMillan TA et al. 1988 Nov 25 (PMID:3182847);
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
05/08/2020
EXPERT CURATION (DATE)
Definitive
11/08/2019
EVIDENCE SUMMARY
The relationship between GCDH and glutaryl CoA dehydrogenase deficiency was evaluated using the ClinGen Clinical Validity Framework as of October 22, 2019. GCDH encodes glutaryl CoA dehydrogenase, a mitochondrial matrix enzyme composed of four identical subunits. This enzyme catalyzes the oxidative decarboxylation of glutaryl-CoA - an intermediate in the metabolism of lysine, hydroxylysine and tryptophan - to crotonyl-CoA and carbon dioxide. Deficiency of GCDH activity causes glutaric acidemia type 1 (GA-1), an autosomal recessive disorder. GA-1 is characterized by macrocephaly, acute encephalopathic crises and progressive movement disorders caused by striatal degeneration, typically with onset between the ages of 6-18 months, and often triggered by an intercurrent infection. Affected individuals present with elevated levels of glutaric acid, 3-hydroxy-glutaric acid, glutaconic acid and glutarylcarnitine and be classified as high excreters or low excreters based on the urine glutaric acid level (Larson and Goodman, 2019, PMID 31536184). Biallelic variants in GCDH were first reported in 1995 (Greenberg et al, PMID 7795610; Goodman et al, PMID 8541831). Since then, around 200 variants have been identified in GCDH. Data from 9 probands who are homozygous or compound heterozygous for GCDH variants were curated, including 9 unique variants (missense, nonsense, frameshift, splicing) (Greenberg et al, 1995, PMID 7795610; Goodman et al, 1995, PMID 8541831; Anikster et al, 1996, PMID 8900228; Moseilhy et al, 2017, PMID 27476540; Zayed et al, 2019, PMID 31062211). One of these variants, c.91+5G>T, segregates in multiple closely related kindreds of an Ojibway-speaking genetic isolate of native Americans living in the Island Lake region of northern Manitoba and nearby communities of northwestern Ontario. (Greenberg et al, 1995, PMID 7795610). An inframe deletion with a dominant-negative impact has also been reported (PMID 22231382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of GCDH which is consistent with the biochemical abnormalities observed in individuals with GCDH deficiency (PMIDs 8287562, 8541831); functional studies (Bross et al, 2012, PMID 22231382; Ribeiro et al, 2019, PMID 31491587), the biochemical and clinical features of a Gcdh knock out mouse (Koeller et al, 2002, PMID 11854167; Zinnanti et al, 2006, PMID 16446282) and biochemical findings in the Egyptian fruit-eating bat which has GCDH deficiency in liver and kidney (McMillan et al, 1998, PMID 3182847). In summary, GCDH is definitively associated with glutaryl CoA dehydrogenase deficiency (GA-1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.