Submissions for variant NM_000151.4(G6PC1):c.910G>A (p.Val304Ile)

gnomAD frequency: 0.00011  dbSNP: rs768385469

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196826	SCV000251524	uncertain significance	not provided	2017-10-13	criteria provided, single submitter	clinical testing	p.Val304Ile (GTC>ATC): c.910 G>A in exon 5 of the G6PC gene (NM_000151.2). The V304I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V304I 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 not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. However, missense mutations in nearby residues (R295C, S298P) have been reported in association with glycogen storage disease 1a, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001240860	SCV001413837	uncertain significance	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 304 of the G6PC protein (p.Val304Ile). This variant is present in population databases (rs768385469, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with G6PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 214463). 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 not expected to disrupt G6PC protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on G6PC function (PMID: 34258141). 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.
Fulgent Genetics, Fulgent Genetics	RCV001240860	SCV002783094	uncertain significance	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-05-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020398	SCV004875739	likely benign	not specified	2021-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000196826	SCV001928940	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000196826	SCV001973466	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001240860	SCV002093327	uncertain significance	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2018-05-03	no assertion criteria provided	clinical testing