Gene Validity Curation

AGPS - rhizomelic chondrodysplasia punctata

Gene: AGPS (HGNC:327)
Classification - 10/04/2019
Disease: rhizomelic chondrodysplasia punctata (MONDO_0015776)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Peroxisomal Disorders EP
Evidence Summary: The relationship between AGPS and rhizomelic chondrodysplasia punctate (RCDP), an autosomal recessive peroxisomal disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 20, 2019. AGPS encodes alkylglycerone-phosphate synthase (also known as alkyldihroxyacetonephosphate synthase, ADHAPS, alkyl-DHAP synthase), a peroxisomal enzyme catalyzing the second (last) step of plasmalogen synthesis. Deficiency of plasmalogens is a feature of RCDP. Variants in AGPS causing RCDP were first reported in 1998 (de Vet et al, PMID 9553082). Data from 7 patients with 8 unique variants (all missense except for one frameshift resulting from a deletion detected in cDNA but genomic variant unknown) from five publications were curated (de Vet et al, 1998, PMID 9553082; de Vet et al, 1999, PMID 10553003; Thai et al, 2001, PMID 11152660; Itzkovitz et al, 2012, PMID 21990100; Noguchi et al, 2014, PMID 24849933). A total of 5.5 points were awarded for genetic evidence (note that this includes 2 points for a case for which the causative variant is unknown, and therefore the case could not be included in the summary matrix, but which appeared to be homozygous for a 128bp deletion in AGPS cDNA; PMID 10553003) The relationship between AGPS and RCDP is supported by experimental evidence including the biochemical function of AGPS which is consistent with the low levels of plasmalogens observed in individuals with RCDP (Brown et al, 1982, PMID 7096336; Nagan et al, 1997, PMID 9114014); the physical interaction of alkylglycerone-phosphate synthase with glyceronephosphate O-acyltransferase (encoded by GNPAT) which catalyzes the first step of plasmalogen synthesis (Biermann et al, 1999, PMID 102158610); the finding that the activity and level glyceronephosphate O-acyltransferase is dependent on the physical presence of alkylglycerone-phosphate synthase (de Vet et al, 1999, PMID 10553003; Itzkovitz et al, PMID 21990100); the knowledge that other genes with a role in plasmalogen synthesis (GNPAT, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Hajra et al, 1995, PMID 8685243; Braverman et al, 1997, PMID 9090381; Braverman et al, 2012, PMID 20301447); the finding of reduced levels of AGPS cDNA and protein in patients with RCDP (Noguchi et al, 2014, PMID 24849933); and the features of a natural and two knock out mouse models (Liegel et al, 2011, PMID 21353609; Liegel et al, 2014, PMID 25197626). More evidence may be available but the maximum points for experimental evidence (6 points) have been reached. While the total points, 11.5, is at the high end of the range for a “moderate” gene-disease clinical validity classification, the Peroxisomal disorders GCEP upgraded the classification to “Definitive” based on the available evidence, including the wealth of experimental evidence. In summary, AGPS is definitively associated with autosomal recessive rhizomelic chondrodysplasia punctata. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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
3.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
3.5
Itzkovitz B et al. 2012 Jan (PMID:21990100); de Vet EC et al. 1998 Apr 24 (PMID:9553082); Noguchi M et al. 2014 Jul (PMID:24849933); Thai TP et al. 2001 Jan 15 (PMID:11152660);
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) 3.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 4
2
2
Nagan N et al. 1997 Apr 29 (PMID:9114014); Brown AJ et al. 1982 Aug 10 (PMID:7096336); Braverman N et al. 1997 Apr (PMID:9090381); Hajra AK et al. 1995 (PMID:8685243);
Protein Interaction 0.5 0 - 2 1 1
Biermann J et al. 1999 Apr (PMID:10215861);
Expression 0.5 0 - 2 1 0.5
Noguchi M et al. 2014 Jul (PMID:24849933);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Liegel R et al. 2011 May (PMID:21353609); Liegel RP et al. 2014 (PMID:25197626);
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 3.5 6 9.5 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
10/04/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Definitive
10/04/2019
REASON(S) FOR CHANGE
An additional case (Patient 2, PMID 10553003) could not be entered into the GCI but was awarded 2 points - see evidence summary). Therefore, the total points = 11.5, at the upper end of "Moderate". The classification was upgraded to “Definitive” based on the available evidence, including the wealth of experimental evidence.
EXPERT CURATION (DATE)
Definitive
10/04/2019
EVIDENCE SUMMARY
The relationship between AGPS and rhizomelic chondrodysplasia punctate (RCDP), an autosomal recessive peroxisomal disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 20, 2019. AGPS encodes alkylglycerone-phosphate synthase (also known as alkyldihroxyacetonephosphate synthase, ADHAPS, alkyl-DHAP synthase), a peroxisomal enzyme catalyzing the second (last) step of plasmalogen synthesis. Deficiency of plasmalogens is a feature of RCDP. Variants in AGPS causing RCDP were first reported in 1998 (de Vet et al, PMID 9553082). Data from 7 patients with 8 unique variants (all missense except for one frameshift resulting from a deletion detected in cDNA but genomic variant unknown) from five publications were curated (de Vet et al, 1998, PMID 9553082; de Vet et al, 1999, PMID 10553003; Thai et al, 2001, PMID 11152660; Itzkovitz et al, 2012, PMID 21990100; Noguchi et al, 2014, PMID 24849933). A total of 5.5 points were awarded for genetic evidence (note that this includes 2 points for a case for which the causative variant is unknown, and therefore the case could not be included in the summary matrix, but which appeared to be homozygous for a 128bp deletion in AGPS cDNA; PMID 10553003) The relationship between AGPS and RCDP is supported by experimental evidence including the biochemical function of AGPS which is consistent with the low levels of plasmalogens observed in individuals with RCDP (Brown et al, 1982, PMID 7096336; Nagan et al, 1997, PMID 9114014); the physical interaction of alkylglycerone-phosphate synthase with glyceronephosphate O-acyltransferase (encoded by GNPAT) which catalyzes the first step of plasmalogen synthesis (Biermann et al, 1999, PMID 102158610); the finding that the activity and level glyceronephosphate O-acyltransferase is dependent on the physical presence of alkylglycerone-phosphate synthase (de Vet et al, 1999, PMID 10553003; Itzkovitz et al, PMID 21990100); the knowledge that other genes with a role in plasmalogen synthesis (GNPAT, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Hajra et al, 1995, PMID 8685243; Braverman et al, 1997, PMID 9090381; Braverman et al, 2012, PMID 20301447); the finding of reduced levels of AGPS cDNA and protein in patients with RCDP (Noguchi et al, 2014, PMID 24849933); and the features of a natural and two knock out mouse models (Liegel et al, 2011, PMID 21353609; Liegel et al, 2014, PMID 25197626). More evidence may be available but the maximum points for experimental evidence (6 points) have been reached. While the total points, 11.5, is at the high end of the range for a “moderate” gene-disease clinical validity classification, the Peroxisomal disorders GCEP upgraded the classification to “Definitive” based on the available evidence, including the wealth of experimental evidence. In summary, AGPS is definitively associated with autosomal recessive rhizomelic chondrodysplasia punctata. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.