ClinVar Miner

Submissions for variant NM_000151.4(G6PC):c.562G>A (p.Gly188Ser) (rs80356482)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197003 SCV000251527 pathogenic not provided 2016-10-17 criteria provided, single submitter clinical testing The G188S missense pathogenic variant in the G6PC gene has been reported previously in association with glycogen storage disease type 1a (Lei et al., 1995). Expression studies found that the G188S mutation abolishes G6Pase activity (Lei et al., 1995). Furthermore, G188S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and another missense mutation at the same position (G188R) has also been reported in association with glycogen storage disease type 1a. Therefore, we interpret G188S to be a pathogenic variant. The variant is found in MITONUC-MITOP panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000587142 SCV000695638 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121410, which does not exceed the predicted maximum expected allele frequency for a pathogenic G6PC variant of 1/577. The variant of interest has been reported in affected individuals via publications, along with a reputable clinical laboratory citing the variant as "pathogenic." In addition, multiple functional studies indicate the variant to inactivate G6Pase enzyme activity. Furthermore, another variant at this position, c.562G>C (p.Gly188Arg) has been reported as pathogenic. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000587142 SCV000776252 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 188 of the G6PC protein (p.Gly188Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 4 of the G6PC coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs80356482, ExAC 0.001%). This variant has been reported in several individuals affected with glycogen storage disease type 1A, being found in combination with another G6PC variant in two of them (PMID: 24565827, 7573034, Invitae). This variant is also known as c.641G>A or G641A in the literature. ClinVar contains an entry for this variant (Variation ID: 214465). Experimental studies have shown that this missense change results in reduced levels of G6PC transcript and abolishes enzyme activity (PMID: 11739393). A different missense substitution at this codon (p.Gly188Arg) has been determined to be pathogenic (PMID: 10960498, 8733042, 10834516, 11739393). This suggests that the glycine residue is critical for G6PC protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000587142 SCV001163786 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000587142 SCV001251515 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter research The c.562G>A (p.G188S) missense variant has been reported in individuals with glycogen storage disease type Ia (PMID: 7573034; 12373566; 24565827).
Counsyl RCV000587142 SCV000791230 likely pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-05-14 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.