ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.79del (p.Gln27fs) (rs80356479)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000199426 SCV000224157 pathogenic not provided 2014-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000199426 SCV000251528 pathogenic not provided 2018-06-20 criteria provided, single submitter clinical testing The c.79delC pathogenic variant in the G6PC gene has been reported previously previously (as 158delC/35X due to alternative nomenclature) in the compound heterozygous state, along with another loss-of-function variant, in a few individuals with glycogen storage disease type 1a (Lei et al., 1995; Shieh et al., 2002; Kishnani et al., 2009). The c.79delC variant causes a frameshift starting with codon Glutamine 27, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Gln27ArgfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.79delC variant is observed in 15/277218 (0.005%) alleles in large population cohorts, with no homozygotes reported (Lek et al., 2016). We interpret c.79delC as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000173073 SCV000402975 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2017-04-27 criteria provided, single submitter clinical testing The G6PC c.79delC (p.Gln27ArgfsTer9) variant results in a frameshift and is predicted to result in premature termination of the protein. The variant is also described in the literature as c.77delC or 158delC. Koeberl et al. (2009) describe the p.Gln27ArgfsTer9 variant as a common variant occurring in up to 5% of Caucasian individuals with glycogen storage disease type 1a. The p.Gln27ArgfsTer9 variant has been reported in five studies in which it is found in a total of 14 individuals including in seven in a homozygous state and seven in a compound heterozygous state (Chevalier-Porst et al. 1996; Rake et al. 1999; Shieh et al. 2002; Angaroni et al. 2004; Kishnani et al. 2009). The variant was additionally found in 7/192 disease alleles in two studies where zygosity data were not available (Lei et al. 1995; Seydewitz et al. 2000). Control data are unavailable for this variant which is reported at a frequency of 0.00235 in the African American population of the Exome Sequencing Project. Several studies report very low or undetectable enzyme activity in liver biopsy specimens indicating the inactivation of the enzyme by the p.Gln27ArgfsTer9 variant (Lei et al. 1995; Chevalier-Porst et al. 1996; Seydewitz et al. 2000; Rake et al. 1999). Chevalier-Porst et al. (1996) also described elevated glycogen content in the liver in an individual who was homozygous for the p.Gln27ArgfsTer9 variant. Based on the collective evidence, the p.Gln27ArgfsTer9 variant is classified as pathogenic for glycogen storage disease type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173073 SCV000695641 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-07-08 criteria provided, single submitter clinical testing Variant summary: The G6PC c.79delC (p.Gln27Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent G6PC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121400 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). There are multiple GSD1a patients reported in the literature who carried the variant as homozygous or heterozygous indicating the pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000173073 SCV000947971 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln27Argfs*9) in the G6PC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768209865, ExAC 0.01%). This variant has been observed in several individuals affected with glycogen storage disease (PMID: 28397058, 16435186, 11739393, 10094563). This variant is also known as 158delC in the literature. ClinVar contains an entry for this variant (Variation ID: 21062). Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000173073 SCV001163776 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000173073 SCV001194026 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-11-15 criteria provided, single submitter clinical testing NM_000151.3(G6PC):c.79delC(Q27Rfs*9) is classified as pathogenic in the context of type Ia glycogen storage disease. Sources cited for classification include the following: PMID 10834516, 12373566, 10874313, 20532819, 23352793, 7573034, 17994282 and 11949931. Classification of NM_000151.3(G6PC):c.79delC(Q27Rfs*9) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449697 SCV001652950 pathogenic Glycogen storage disease, type I 2020-06-25 criteria provided, single submitter clinical testing The p.Gln27ArgfsX9 variant in G6PC has been reported in at least 4 homozgyous and 2 compound heterozygous individuals with Glycogen storage disease, and reported without allele state information in an additional 6 individuals with Glycogen storage disease (Lei 1995 PMID: 7573034, Chevalier-Porst 1996 PMID: 8733042, Rake 1999 PMID: 10094563, Angaroni 2004 PMID: 15542400). It has also been identified in 0.011% (14/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is reported in ClinVar (Variation ID: 21062). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 27 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the G6PC gene is an established disease mechanism in autosomal recessive Glycogen storage disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen storage disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting.
GeneReviews RCV000173073 SCV000040463 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-08-25 no assertion criteria provided literature only

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