Submissions for variant NM_000170.3(GLDC):c.2891dup (p.Tyr964Ter)

gnomAD frequency: 0.00001  dbSNP: rs386833572

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049583	SCV000695759	likely pathogenic	Non-ketotic hyperglycinemia	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.2891dupA (p.Tyr964X) 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. The variant allele was found at a frequency of 4e-06 in 251228 control chromosomes (gnomAD and Kure_2006). c.2891dupA has been reported in the literature as a compound heterozygous genotype together with an exon 1 deletion in an individual affected with Non-Ketotic Hyperglycinemia (e.g. Kure_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049583	SCV003440917	pathogenic	Non-ketotic hyperglycinemia	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr964*) in the GLDC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the GLDC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with glycine encephalopathy (PMID: 16450403). This variant is also known as c.2891insA. ClinVar contains an entry for this variant (Variation ID: 56172). This variant disrupts a region of the GLDC protein in which other variant(s) (p.Gly994Arg) have been determined to be pathogenic (PMID: 26179960, 27362913, 28244183). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049583	SCV000081934	probable-pathogenic	Non-ketotic hyperglycinemia		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.