Gene Validity Curation

AHCY - hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Gene: AHCY (HGNC:343)
Classification - 06/29/2020
Disease: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (MONDO_0013404)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: AHCY was first reported in relation to autosomal recessive hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase in 2004 (Baric I, et al., 2004, PMID: 15024124). Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, with biochemical abnormalities of marked elevations in plasma SAH, SAM, methionine and creatine kinase accompanied by a significant decrease in the SAM/SAH ratio. At least 10 variants (mostly missense but also nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 8 probands in 8 publications (PMIDs: 15024124, 16736098, 20852937, 22959829, 30121674, 26527160, 26095522, 27848944). Variants in this gene segregated with disease in two additional family members. This gene-disease relationship is supported by its biochemical function. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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 2
4
7.35
Baric I et al. 2004 Mar 23 (PMID:15024124); Buist NR et al. 2006 Aug (PMID:16736098);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
3.35
Grubbs R et al. 2010 Dec (PMID:20852937); Honzík T et al. 2012 Nov (PMID:22959829); Stender S et al. 2015 Dec (PMID:26527160); Trujillano D et al. 2017 Feb (PMID:27848944); Judkins AJ et al. 2018 Aug 17 (PMID:30121674); Strauss KA et al. 2015 Sep-Oct (PMID:26095522);
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) 7.35
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
2
2
DE LA HABA G et al. 1959 Mar (PMID:13641268);
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 1 0.5 0.5
Dickinson ME et al. 2016 Sep 22 (PMID:27626380);
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) 2.5

 


 

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 7.35 2.5 9.85 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)
Moderate
04/24/2020
EXPERT CURATION (DATE)
Moderate
06/29/2020
EVIDENCE SUMMARY
AHCY was first reported in relation to autosomal recessive hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase in 2004 (Baric I, et al., 2004, PMID: 15024124). Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, with biochemical abnormalities of marked elevations in plasma SAH, SAM, methionine and creatine kinase accompanied by a significant decrease in the SAM/SAH ratio. At least 10 variants (mostly missense but also nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 8 probands in 8 publications (PMIDs: 15024124, 16736098, 20852937, 22959829, 30121674, 26527160, 26095522, 27848944). Variants in this gene segregated with disease in two additional family members. This gene-disease relationship is supported by its biochemical function. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.