ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.113A>T (p.Asp38Val)

gnomAD frequency: 0.00005  dbSNP: rs104894565
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507730 SCV000603763 pathogenic not specified 2016-09-30 criteria provided, single submitter clinical testing
Invitae RCV000012784 SCV000776251 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 38 of the G6PC protein (p.Asp38Val). This variant is present in population databases (rs104894565, gnomAD 0.002%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 8733042, 9359038, 10070617, 10834516, 11310582). ClinVar contains an entry for this variant (Variation ID: 12004). 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 G6PC protein function. Experimental studies have shown that this missense change affects G6PC function (PMID: 9359038, 11739393). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012784 SCV000917379 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-02-01 criteria provided, single submitter clinical testing Variant summary: G6PC c.113A>T (p.Asp38Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246454 control chromosomes in gnomAD and literature. This frequency is not significantly higher than expected for a pathogenic variant in G6PC causing Glycogen Storage Disease Type Ia (8.1e-06 vs 1.70E-03), allowing no conclusion about variant significance. c.113A>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia, including one confirmed homozygote (Chevalier-Porst_1996, Stroppiano_1999, Reis_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolished enzymatic activity (Chevalier-Porst_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000012784 SCV001163777 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
GeneDx RCV002243637 SCV002513755 pathogenic not provided 2022-05-12 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on enzyme activity (Parvari et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11739393, 28074886, 34258141, 8733042, 9359038)
OMIM RCV000012784 SCV000033024 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 1996-05-01 no assertion criteria provided literature only
Counsyl RCV000012784 SCV001132392 likely pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2018-06-25 no assertion criteria provided clinical testing
Natera, Inc. RCV000012784 SCV002093291 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-03-17 no assertion criteria provided clinical testing

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