Submissions for variant NM_000170.3(GLDC):c.2414G>A (p.Trp805Ter)

dbSNP: rs386833557

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049485	SCV002155568	pathogenic	Glycine encephalopathy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp805*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 12402263). ClinVar contains an entry for this variant (Variation ID: 56076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002243691	SCV002513145	pathogenic	not provided	2022-04-26	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: 25525159, 12402263)
PreventionGenetics, part of Exact Sciences	RCV003390751	SCV004119743	pathogenic	GLDC-related disorder	2022-10-25	criteria provided, single submitter	clinical testing	The GLDC c.2414G>A variant is predicted to result in premature protein termination (p.Trp805*). This variant was reported in the heterozygous state in female with transient neonatal hyperglycinemia (Patient 1, Kure et al. 2002. PubMed ID: 12402263). Of note, another variant leading to the same loss of function variant [c.2415G>A (p.Trp805*)] was reported in the compound heterozygous state in another female with severe nonketoric hyperglycinemia (Supplemental Table 1, Swanson et al. 2015. PubMed ID: 26179960). The c.2414G>A (p.Trp805*) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLDC are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049485	SCV000081919	probable-pathogenic	Glycine encephalopathy		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.