Submissions for variant NM_000170.3(GLDC):c.1705G>A (p.Ala569Thr)

gnomAD frequency: 0.00419  dbSNP: rs151268759

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224411	SCV000281015	likely benign	not provided	2016-04-12	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000224411	SCV000493519	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GLDC: BS2
Invitae	RCV000454365	SCV000636363	benign	Non-ketotic hyperglycinemia	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271475	SCV000695757	benign	not specified	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.1705G>A (p.Ala569Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 252282 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) phenotype (0.0031), strongly suggesting that the variant is benign. c.1705G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) without strong evidence for causality (e.g. Kure_2006, Narisawa_2012, Swanson_2015). Functional studies assessing the impact of the variant on protein function have reported 40-75% enzyme activity and normal protein levels (Swanson_2015, Narisawa_2012). Nine assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (benign n=3, likely benign n=4, VUS n=1, likely pathogenic n=1). Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics	RCV000224411	SCV000842217	benign	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000454365	SCV001330666	likely benign	Non-ketotic hyperglycinemia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000454365	SCV001440940	likely benign	Non-ketotic hyperglycinemia	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000224411	SCV001942765	benign	not provided	2018-07-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26179960, 22171071, 16450403, 27362913)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454365	SCV000538035	likely pathogenic	Non-ketotic hyperglycinemia	2016-03-30	flagged submission	clinical testing	The c.1705G>A (p.Ala569Thr) missense variant in the GLDC gene is known and has been previously reported in at least 7 individuals affected with Glycine encephalopathy (Kure et al., 2006; Narisawa et al., 2012; Swanson et al., 2015). This variant has often been described in trans with another pathogenic variant (Pro765Ser, Pro304Leu) (Kure et al., 2006; Swanson et al., 2015). Multiple in vitro functional assays have demonstrated this variant results in reduced or undetectable GLDC activity (Narisawa et al., 2012; Swanson et al., 2015). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.558%; 1000 Genomes = 0.7%; and ExAC = 0.454%). Therefore, this collective evidence supports the classification of the c.1705G>A (p.Ala569Thr) as a recessive Likely pathogenic variant for Glycine encephalopathy. We have confirmed this finding in our laboratory using Sanger sequencing.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000454365	SCV000734700	benign	Non-ketotic hyperglycinemia		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000454365	SCV001462762	uncertain significance	Non-ketotic hyperglycinemia	2019-10-09	flagged submission	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224411	SCV001799635	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224411	SCV001929882	likely benign	not provided		no assertion criteria provided	clinical testing