Submissions for variant NM_000170.3(GLDC):c.450C>G (p.Asn150Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003008476	SCV003314033	pathogenic	Glycine encephalopathy	2024-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 150 of the GLDC protein (p.Asn150Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GLDC-related conditions (PMID: 34513771, 35616651). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2098519). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLDC protein function. This variant disrupts the p.Asn150 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15192636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003008476	SCV004038275	likely pathogenic	Glycine encephalopathy	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.450C>G (p.Asn150Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD). c.450C>G has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with severe Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Cao_2021, Hubschmann_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, variants affecting the same amino acid (i.e. p.Asn150Thr, p.Asn150Ser) have been observed in affected individuals (HGMD database) and/or have been classified as pathogenic in ClinVar, suggesting p.Asn150 is likely important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 34513771, 35616651). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.