Submissions for variant NM_000170.3(GLDC):c.1166C>T (p.Ala389Val)

gnomAD frequency: 0.00003  dbSNP: rs121964979

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000012769	SCV000480517	pathogenic	Glycine encephalopathy	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the GLDC c.1166C>T (p.Ala389Val) variant has been identified 25 patients with glycine encephalopathy, including in a homozygous state in 11 patients and in a compound heterozygous state in 14 patients (Applegarth et al. 2004; Dinopoulos et al. 2005; Kure et al. 2006; Swanson et al. 2015; Coughlin et al. 2016). The variant has also been identified in four unaffected family members (Dinopoulos et al. 2005). The p.Ala389Val variant was absent from 300 controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Ala389 residue is conserved. Functional expression studies in COS-7 cells showed that the variant enzyme retained from 7.9% to over 10% of the wild type enzymatic activity which may explain the mild phenotype (Dinopoulos et al. 2005; Swanson et al. 2015). The Ala389 residue is highly conserved. Based on the collective evidence, the p. Ala389Val variant is classified as pathogenic for glycine encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000482511	SCV000568230	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Homozygous individuals in the literature (Applegarth et al., 2004; Dinopooulos et al., 2005) reported to have milder nonketotic hyperglycinemia phenotype or phenotypic variability; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts, and no individuals were reported to be homozygous (gnomAD); This variant is associated with the following publications: (PMID: 26179960, 26749113, 15824356, 15272469, 32421718, 27362913, 16450403)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012769	SCV000636349	pathogenic	Glycine encephalopathy	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 389 of the GLDC protein (p.Ala389Val). This variant is present in population databases (rs121964979, gnomAD 0.008%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 15824356, 16450403, 26179960, 26749113). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11989). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLDC function (PMID: 15824356, 26179960). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000012769	SCV002024844	pathogenic	Glycine encephalopathy	2019-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004629140	SCV005123563	pathogenic	Inborn genetic diseases	2024-05-07	criteria provided, single submitter	clinical testing	The c.1166C>T (p.A389V) alteration is located in exon 9 (coding exon 9) of the GLDC gene. This alteration results from a C to T substitution at nucleotide position 1166, causing the alanine (A) at amino acid position 389 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282552) total alleles studied. The highest observed frequency was 0.007% (9/128976) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other GLDC variant(s) in individual(s) with features consistent with autosomal recessive GLDC-related glycine encephalopathy; in at least one instance, the variants were identified in trans (Kure, 2006; Swanson, 2015; Dinopoulos, 2005). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV004566736	SCV005382830	pathogenic	Glycine encephalopathy 1	2024-10-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV004566736	SCV005679330	pathogenic	Glycine encephalopathy 1	2024-05-09	criteria provided, single submitter	clinical testing
OMIM	RCV004566736	SCV000033004	pathogenic	Glycine encephalopathy 1	2005-04-12	no assertion criteria provided	literature only
Natera, Inc.	RCV000012769	SCV002075782	pathogenic	Glycine encephalopathy	2020-05-20	no assertion criteria provided	clinical testing