ClinVar Miner

Submissions for variant NM_000151.4(G6PC):c.562G>C (p.Gly188Arg) (rs80356482)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000012788 SCV000695639 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-06-22 criteria provided, single submitter clinical testing Variant summary: The G6PC c.562G>C (p.Gly188Arg) variant involves the alteration of a conserved nucleotide located in a transmembrane helix, which are critical for the correct folding, stability, and enzymatic activity of G6Pase (Shieh_2002). 4/4 in silico tools predict a damaging outcome, in addition, the variant is located in the last 3' nucleotide position in exon 4, which 4/5 splice prediction tools predict an impact on splicing. A functional study, Shieh_2002, indicates the variant greatly reduced G6Pase activity. This variant was found in 8/121410 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). Multiple publications have cited the variant in affected compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000012788 SCV000961394 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 188 of the G6PC protein (p.Gly188Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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. This variant is present in population databases (rs80356482, ExAC 0.01%). This variant has been observed in several individuals affected with glycogen storage disease type Ia (PMID: 8733042, 10960498). ClinVar contains an entry for this variant (Variation ID: 12008). This variant has been reported to affect G6PC protein function (PMID: 10612834, 10960498, 11739393). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly188 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been observed in individuals with G6PC-related conditions (PMID: 24565827, 7573034), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000012788 SCV001163787 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000012788 SCV001193873 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-12-20 criteria provided, single submitter clinical testing NM_000151.3(G6PC):c.562G>C(G188R) is classified as pathogenic in the context of glycogen storage disease type Ia. Please note homozygosity for G188R has been reported to be associated with a GSD type Ib-like phenotype with neutropenia.. Sources cited for classification include the following: PMID 23352793, 11058903, 11739393, 8733042, 10612834, 10874313, 12373566 and 10960498. Classification of NM_000151.3(G6PC):c.562G>C(G188R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000012788 SCV000033028 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2000-09-01 no assertion criteria provided literature only
GeneReviews RCV000012788 SCV000040460 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-08-25 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000012788 SCV000485233 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-04-26 no assertion criteria provided clinical testing

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