Gene Validity Curation

ALDH6A1 - developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency

Gene: ALDH6A1 (HGNC:7179)
Classification - 09/27/2019
Disease: developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency (MONDO_0013579)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: The relationship between ALDH6A1 and methylmalonate semialdehyde dehydrogenase deficiency (Autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/18/19. Variants in ALDH6A1 were first reported in humans with this disease as early as 2000 (Chambliss et al., PMID: 10947204). At least 5 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes both minimal case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 10947204, 21863277, 23835272). No segregation information is available. This gene-disease association is also supported by functional evidence, namely that a deficiency in the MMSDH protein would lead to an increase in valine metabolites such as 3-hydroxyisobutyric acid. In summary, there is limited evidence to support this gene-disease relationship. There is the question of whether the additional symptoms of some individuals are related to this disorder, although that is unrelated to the biochemical abnormality. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/27/2019 (SOP Version 7). **This curation is awaiting new published evidence as of 09/27/19 and will require an update when available.
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
1.3
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
1.3
Chambliss KL et al. 2000 Jul (PMID:10947204); Sass JO et al. 2012 May (PMID:21863277); Marcadier JL et al. 2013 Jul 9 (PMID:23835272);
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) 1.3
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Sass JO et al. 2012 May (PMID:21863277);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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) 0.5

 


 

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 1.3 0.5 1.8 NO
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)
Limited
09/27/2019
EXPERT CURATION (DATE)
Limited
09/27/2019
EVIDENCE SUMMARY
The relationship between ALDH6A1 and methylmalonate semialdehyde dehydrogenase deficiency (Autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/18/19. Variants in ALDH6A1 were first reported in humans with this disease as early as 2000 (Chambliss et al., PMID: 10947204). At least 5 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes both minimal case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 10947204, 21863277, 23835272). No segregation information is available. This gene-disease association is also supported by functional evidence, namely that a deficiency in the MMSDH protein would lead to an increase in valine metabolites such as 3-hydroxyisobutyric acid. In summary, there is limited evidence to support this gene-disease relationship. There is the question of whether the additional symptoms of some individuals are related to this disorder, although that is unrelated to the biochemical abnormality. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/27/2019 (SOP Version 7). **This curation is awaiting new published evidence as of 09/27/19 and will require an update when available.