ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1705G>A (p.Ala569Thr) (rs151268759)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000224411 SCV000842217 benign not provided 2017-09-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224411 SCV000493519 likely pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
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.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000454365 SCV000734700 benign Non-ketotic hyperglycinemia no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000224411 SCV000695757 likely benign not provided 2017-06-29 criteria provided, single submitter clinical testing Variant summary: The GLDC c.1705G>A (p.Ala569Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide and it is located in the Pyridoxal phosphate-dependent transferase (IPR015424) (InterPro). 2/3 in silico tools predict benign outcome for this variant. Functional studies showed 40-75% enzyme residual activity and normal protein levels (Swanson_AON_2015, Narisawa_HMG_2012). This variant was found in 475/121878 control chromosomes from ExAC and publications (including 4 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.022377 (148/6614). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic GLDC variant (0.0030619). This variant has not been reported as a founder mutation, thus it is likely a benign polymorphism found primarily in the populations of European (Finnish) origin based on its frequency in the controls. Presence of homozygotes is evidence favoring against pathogenicity because ExAC rules out individuals with severe pediatric diseases. This variant was found in three patients with nonketotic hyperglycinemia without strong evidence for causality (Kure_MG_2006; Swanson_AON_2015). In ClinVar while one clinical laboratory has classified as likely benign, other two labs has classified it as likely pathogenic (one lab has indicated that the classification was based on one functional study among other evidences; however, the functional result in that study was later corrected [Swanson_AON_erratum_2015]). Additionally, one database (LOVD) has concluded that this variant does not affect function. Taken together, this variant is classified as likely benign.
Invitae RCV000454365 SCV000636363 benign Non-ketotic hyperglycinemia 2018-01-17 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000454365 SCV000538035 likely pathogenic Non-ketotic hyperglycinemia 2016-03-30 criteria provided, single submitter 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.