ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.128del (p.Asp43fs) (rs1251443902)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667354 SCV000791788 likely pathogenic Non-ketotic hyperglycinemia 2017-05-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000667354 SCV000966894 pathogenic Non-ketotic hyperglycinemia 2018-02-07 criteria provided, single submitter clinical testing The p.Asp43AlafsX48 (NM_000170.2 c.128delA) variant in GLDC has been previously reported in 1 compound heterozygous individual with glycine encephalopathy (Swan son 2015), and was absent from large population studies. This variant is predict ed to cause a frameshift, which alters the protein?s amino acid sequence beginni ng at position 43 and leads to a premature termination codon 48 amino acids down stream. This alteration is then predicted to lead to a truncated or absent prote in. Biallelic loss of function of the GLDC gene is associated with glycine encep halopathy. In summary, the p.Asp43AlafsX48 variant meets our criteria to be clas sified as pathogenic for glycine encephalopathy in an autosomal recessive manner based on its occurrence in trans with another pathogenic variant in an affected individual and its predicted impact on the protein.
Invitae RCV000667354 SCV001385089 pathogenic Non-ketotic hyperglycinemia 2019-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp43Alafs*48) in the GLDC gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed as heterozygous in an individual affected with encephalopathy (PMID: 30609409). ClinVar contains an entry for this variant (Variation ID: 552137). Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667354 SCV001519600 pathogenic Non-ketotic hyperglycinemia 2021-03-08 criteria provided, single submitter clinical testing Variant summary: GLDC c.128delA (p.Asp43AlafsX48) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.3e-05 in 150762 control chromosomes (gnomAD v3.1). c.128delA has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Swanson_2015, Coughlin_2017) and is included as a pathogenic variant in targeted testing panels for Amish communities (e.g. Crowgey_2019, Clinic for Special Children). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001592846 SCV001815464 pathogenic not provided 2019-06-11 criteria provided, single submitter clinical testing Has been reported (as c.127_128delAfs*47, due to use of alternate nomenclature) in trans with a splice site variant in a patient with severe nonketotic hyperglycinemia (Swanson et al., 2015); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30609409, 26179960)

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.