Submissions for variant NM_000170.3(GLDC):c.437C>A (p.Thr146Lys)

dbSNP: rs376578742

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001389830	SCV000695760	likely pathogenic	Glycine encephalopathy	2022-03-09	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.437C>A (p.Thr146Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes. c.437C>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Bravo-Alonso_2017, Coughlin_2017) and continues to be cited by others (example, Farris_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal GCS-P protein activity in COS7 cells (example, Bravo-Alonso_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389830	SCV001591334	pathogenic	Glycine encephalopathy	2023-06-04	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 27362913, 28244183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs376578742, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 146 of the GLDC protein (p.Thr146Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLDC function (PMID: 28244183). 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) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function. ClinVar contains an entry for this variant (Variation ID: 495700).