ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.189G>A (p.Trp63Ter)

gnomAD frequency: 0.00005  dbSNP: rs764920787
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169341 SCV000220703 likely pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2014-09-17 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169341 SCV001220526 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp63*) in the G6PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 7573034, 11949931). ClinVar contains an entry for this variant (Variation ID: 188966). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169341 SCV002819522 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2022-12-14 criteria provided, single submitter clinical testing Variant summary: G6PC c.189G>A (p.Trp63X), also referred to as c.268G>A, results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251420 control chromosomes (gnomAD). c.189G>A has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ia (e.g. Lei_1995, Rake_1999, Rake_2000). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in little to no protein expression, approximately 2% of the WT protein (Plona_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000169341 SCV002093293 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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