Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GLDC : glycine encephalopathy

HGNC:4313 | MONDO_0011612
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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
Conter C et al. 2006 Feb (PMID:16601880); Ezgu F et al. 2014 Mar (PMID:24407464); Swanson MA et al. 2015 Oct (PMID:26179960); Coughlin CR et al. 2017 Jan (PMID:27362913); Bravo-Alonso I et al. 2017 Jun (PMID:28244183);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Bravo-Alonso I et al. 2017 Jun (PMID:28244183); Kure S et al. 1991 Feb 14 (PMID:1996985);
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) 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
Coughlin CR et al. 2017 Jan (PMID:27362913); Kikuchi G et al. 2008 (PMID:18941301);
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 2 2
Pai YJ et al. 2015 Mar 4 (PMID:25736695);
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) 4



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between GLDC and glycine encephalopathy (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of October 19th, 2018. Variants in GLDC, which encodes the P-protein (glycine decarboxylase) of the glycine cleavage system, were first reported in humans with this disease as early as 1991 (Kure et al, PMID 1996985). At least 300 unique variants (52% missense mutations, 11% nonsense mutations, 10% splice-site mutations, 6% small insertions/deletions, and 21% exonic CNVs) have been reported in humans (Coughlin et al, 2017, PMID 27362913; van Hove et al, 2013, PMID 20301531). Variants in this gene have been reported in about 80% of probands with glycine encephalopathy (nonketotic hyperglycinemia, NKH); most of the remaining patients have variants in AMT which encodes the T-protein of the glycine cleavage system. Ten patients and 12 unique variants in GLDC are included here (Kure et al, 1991, PMID 1996985; Conter et al, 2006, PMID 16601880; Ezgu et al, 2014, PMID 24407464; Swanson et al, 2015, PMID 26179960; Coughlin et al, 2017, PMID 27362913). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, while most variants are private, a founder variant, p.Ser564Ile, accounts for about 70% of GLDC variants in the Finnish population (Kure et al, 1992, PMID 1634607), and other recurrent variants have been reported (Coughlin et al, 2017, PMID 27362913). The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the P protein (glycine carboxylase) in the glycine cleavage system, and a mouse model (Pai et al, 2015, PMID 25736695). In summary, GLDC is definitively associated with autosomal recessive glycine encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.