Gene Validity Curation

GNPAT - rhizomelic chondrodysplasia punctata

Gene: GNPAT (HGNC:4416)
Classification - 02/07/2020
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 GNPAT and rhizomelic chondrodysplasia punctata (RCDP), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 16, 2019. GNPAT encodes glyceronephosphate O-acyltransferase (also known as dihydroxyacetone phosphate acyltransferase; DHAPAT, DAPAT), a peroxisomal enzyme involved in the synthesis of plasmalogens. Deficiency of plasmalogens is a feature of RCDP. Variants in GNPAT causing RCDP were first reported in 1998 (Ofman et al, PMID 9536089). Data from 13 patients with 12 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Ofman et al, 1998, PMID 9536089; Ofman et al, 2001, PMID 11237722; Thai et al, 2001, PMID 11152660; Nimmo et al, 2010, PMID 20583171; Itzkovitz et al, 2012, PMID 21990100). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between GNPAT and RCDP is supported by experimental evidence including the biochemical function of GNPAT which is consistent with the biochemical features of the disease (Hajra et al, 1995; PMID 8685243), that other genes with a role in plasmalogen synthesis (AGPS, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Braverman et al, 1997, PMID 9090381; Itzkovitz et al, 2012, PMID 21990100), and a knock out mouse model which recapitulates the features of the condition (Rodemer et al, 2003, PMID 12874108; Teigler et al, 2009, PMID 19270340). In summary, GNPAT is definitively associated with RCDP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on February 7, 2020.
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
14
12
Ofman R et al. 1998 May (PMID:9536089); Itzkovitz B et al. 2012 Jan (PMID:21990100); Ofman R et al. 2001 Mar 2 (PMID:11237722); Nimmo G et al. 2010 Jul (PMID:20583171);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
5.25
Ofman R et al. 1998 May (PMID:9536089); Thai TP et al. 2001 Jan 15 (PMID:11152660); Itzkovitz B et al. 2012 Jan (PMID:21990100); Ofman R et al. 2001 Mar 2 (PMID:11237722);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.2 1
Ofman R et al. 1998 May (PMID:9536089);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
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 3
1.5
1.5
Itzkovitz B et al. 2012 Jan (PMID:21990100); Braverman N et al. 1997 Apr (PMID:9090381); Hajra AK et al. 1995 (PMID:8685243);
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 2 2 2
Rodemer C et al. 2003 Aug 1 (PMID:12874108); Teigler A et al. 2009 Jun 1 (PMID:19270340);
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) 3.5

 


 

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 12 3.5 15.5 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)
Definitive
04/07/2020
EXPERT CURATION (DATE)
Definitive
02/07/2020
EVIDENCE SUMMARY
The relationship between GNPAT and rhizomelic chondrodysplasia punctata (RCDP), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 16, 2019. GNPAT encodes glyceronephosphate O-acyltransferase (also known as dihydroxyacetone phosphate acyltransferase; DHAPAT, DAPAT), a peroxisomal enzyme involved in the synthesis of plasmalogens. Deficiency of plasmalogens is a feature of RCDP. Variants in GNPAT causing RCDP were first reported in 1998 (Ofman et al, PMID 9536089). Data from 13 patients with 12 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Ofman et al, 1998, PMID 9536089; Ofman et al, 2001, PMID 11237722; Thai et al, 2001, PMID 11152660; Nimmo et al, 2010, PMID 20583171; Itzkovitz et al, 2012, PMID 21990100). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between GNPAT and RCDP is supported by experimental evidence including the biochemical function of GNPAT which is consistent with the biochemical features of the disease (Hajra et al, 1995; PMID 8685243), that other genes with a role in plasmalogen synthesis (AGPS, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Braverman et al, 1997, PMID 9090381; Itzkovitz et al, 2012, PMID 21990100), and a knock out mouse model which recapitulates the features of the condition (Rodemer et al, 2003, PMID 12874108; Teigler et al, 2009, PMID 19270340). In summary, GNPAT is definitively associated with RCDP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on February 7, 2020.