Submissions for variant NM_000170.3(GLDC):c.1952A>G (p.His651Arg)

dbSNP: rs386833536

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430656	SCV000520835	likely pathogenic	not provided	2017-10-12	criteria provided, single submitter	clinical testing	The H651R variant in the GLDC gene has been reported previously in association with autosomal recessive nonketotic hyperglycinemia when present in the homozygous state as well as in the heterozygous state in the presence of another nonketotic hyperglycinemia pathogenic gene variant (Conter et al., 2006; Azize et al., 2014). The H651R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H651R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The H651R variant is a strong candidate for a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049464	SCV004295993	pathogenic	Glycine encephalopathy	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 651 of the GLDC protein (p.His651Arg). 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: 27362913). ClinVar contains an entry for this variant (Variation ID: 56055). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049464	SCV000081898	probable-pathogenic	Glycine encephalopathy		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.