Submissions for variant NM_000170.3(GLDC):c.499G>T (p.Glu167Ter)

gnomAD frequency: 0.00012  dbSNP: rs191905539

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412474	SCV000636407	pathogenic	Glycine encephalopathy	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu167*) in the GLDC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). This variant is present in population databases (rs191905539, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycine encephalopathy, also known as non-ketotic hyperglycinemia (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 370365). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412474	SCV000695761	pathogenic	Glycine encephalopathy	2020-07-02	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.499G>T (p.Glu167X) 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 2e-05 in 251296 control chromosomes. c.499G>T has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) in the homozygous and compound heterozygous states (Swanson_2015, Coughlin_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000624546	SCV000741325	pathogenic	Inborn genetic diseases	2021-08-23	criteria provided, single submitter	clinical testing	The c.499G>T (p.E167*) alteration, located in exon 4 (coding exon 4) of the GLDC gene, consists of a G to T substitution at nucleotide position 499. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 167. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251296) total alleles studied. The highest observed frequency was 0.016% (1/6132) of Other alleles. This mutation has been detected in the homozygous and compound heterozygous states in individuals with nonketotic hyperglycemia (Swanson, 2015). Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001556638	SCV001778253	pathogenic	not provided	2022-05-28	criteria provided, single submitter	clinical testing	Nonsense 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26179960)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000412474	SCV004847398	likely pathogenic	Glycine encephalopathy	2024-01-01	criteria provided, single submitter	clinical testing	The p.Glu167X variant in GLDC has been reported in the compound heterozygous state or homozygous state in at least 3 individuals with glycine encephalopathy (Swanson 2015 PMID: 26179960, Coughlin 2017 PMID: 27362913). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 370365) and has been identified in 0.12% (19/15276) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 167, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the GLDC gene is an established disease mechanism in autosomal recessive glycine encephalopathy, also known as nonketotic hyperglycinemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycine encephalopathy. ACMG/AMP Criteria applied: PVS1, PM3.
Fulgent Genetics, Fulgent Genetics	RCV005044608	SCV005679339	pathogenic	Glycine encephalopathy 1	2024-03-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000412474	SCV000485665	likely pathogenic	Glycine encephalopathy	2016-10-31	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000412474	SCV000536876	pathogenic	Glycine encephalopathy	2016-06-29	no assertion criteria provided	research
Natera, Inc.	RCV000412474	SCV001458172	pathogenic	Glycine encephalopathy	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745365	SCV005350886	pathogenic	GLDC-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The GLDC c.499G>T variant is predicted to result in premature protein termination (p.Glu167*). This variant was reported as a recurrent variant for nonketotic hyperglycinemia (see, for example, Swanson et al. 2015. PubMed ID: 26179960). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in GLDC are expected to be pathogenic. This variant is interpreted as pathogenic.