ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.1012G>T (p.Val338Phe)

dbSNP: rs367727229
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169319 SCV000220649 likely pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2014-08-27 criteria provided, single submitter literature only
Invitae RCV000169319 SCV001235844 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2021-10-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 338 of the G6PC protein (p.Val338Phe). This variant is present in population databases (rs367727229, gnomAD 0.003%). This missense change has been observed in individual(s) with glycogen storage disease type Ia (PMID: 10070617, 10094563, 11058903, 11310582). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188945). 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: 11739393). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169319 SCV001363566 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2019-04-05 criteria provided, single submitter clinical testing Variant summary: G6PC c.1012G>T (p.Val338Phe) results in a non-conservative amino acid change in the Helical 9 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246074 control chromosomes. c.1012G>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (Trioche_2000, Matern_2002). 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 <10% of normal phosphohydrolase activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One clinical laboratory submitted a classification of Likely pathogenic to ClinVar in 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000169319 SCV002093335 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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