Submissions for variant NM_000170.3(GLDC):c.2518A>G (p.Met840Val)

gnomAD frequency: 0.00011  dbSNP: rs781693346

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000263401	SCV000480498	uncertain significance	Glycine encephalopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000263401	SCV000826820	uncertain significance	Glycine encephalopathy	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 840 of the GLDC protein (p.Met840Val). This variant is present in population databases (rs781693346, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GLDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 367180). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000263401	SCV001530170	uncertain significance	Glycine encephalopathy	2018-08-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV000263401	SCV002791276	uncertain significance	Glycine encephalopathy	2021-08-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004629205	SCV005123564	uncertain significance	Inborn genetic diseases	2024-04-03	criteria provided, single submitter	clinical testing	The c.2518A>G (p.M840V) alteration is located in exon 21 (coding exon 21) of the GLDC gene. This alteration results from a A to G substitution at nucleotide position 2518, causing the methionine (M) at amino acid position 840 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV004696162	SCV005196301	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV004696162	SCV005386868	uncertain significance	not provided	2024-04-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000263401	SCV001458635	uncertain significance	Glycine encephalopathy	2020-01-05	no assertion criteria provided	clinical testing