ClinVar Miner

Submissions for variant NM_000151.4(G6PC):c.248G>A (p.Arg83His) (rs1801176)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000020132 SCV000695637 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-12-30 criteria provided, single submitter clinical testing Variant summary: The G6PC c.248G>A (p.Arg83His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by a functional study showing p.Arg83His abolished G6Pase activity. This variant was found in 3/121296 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients, predominantly in Chinese population. In addition, multiple reputable databases classified this variant as pathogenic. p.Arg83Cys has been shown to associate with GSD1a, suggesting Arg83 is a critical amino acid. Taken together, this variant is classified as pathogenic.
Invitae RCV000020132 SCV000936720 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 83 of the G6PC protein (p.Arg83His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs1801176, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another G6PC variant in individuals affected with glycogen storage disease type Ia (PMID: 7573034, 10797430, 10604148). ClinVar contains an entry for this variant (Variation ID: 38300). Experimental studies have shown that this missense change abrogates G6PC enzyme activity (PMID: 7573034). This variant disrupts the p.Arg83 amino acid residue in G6PC. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23312056, 18008183, 15316959, 15316959, 7623438, 24385852, 10834516), 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 RCV000020132 SCV001163781 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020132 SCV001193972 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-12-13 criteria provided, single submitter clinical testing NM_000151.3(G6PC):c.248G>A(R83H) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 10944847, 7573034, 12373566, 10748407, 7655466, 10797430 and 18449899. Classification of NM_000151.3(G6PC):c.248G>A(R83H) 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.
GeneReviews RCV000020132 SCV000040457 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. RCV000020132 SCV000485166 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2015-12-17 no assertion criteria provided clinical testing

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