Submissions for variant NM_000170.3(GLDC):c.505T>C (p.Ser169Pro)

gnomAD frequency: 0.00001  dbSNP: rs1356375715

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001959050	SCV002245436	pathogenic	Glycine encephalopathy	2023-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 169 of the GLDC protein (p.Ser169Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 27362913). 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: 1459544). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226512	SCV003922552	uncertain significance	not specified	2023-03-23	criteria provided, single submitter	clinical testing	Variant summary: GLDC c.505T>C (p.Ser169Pro) 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 251306 control chromosomes. c.505T>C has been reported in the literature in an individual affected with Non-Ketotic Hyperglycinemia with another likely pathogenic variant in trans (Cloughlin_2017). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001959050	SCV004046063	likely pathogenic	Glycine encephalopathy		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in a patient with glycine encephalopathy (PMID: 27362913). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0032% (1/31402) and is absent in the homozygous state. The c.505T>C (p.Ser169Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.505T>C (p.Ser169Pro) variant is classified as Likely Pathogenic.
GeneDx	RCV004762278	SCV005368970	likely pathogenic	not provided	2024-04-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27362913)