Submissions for variant NM_000151.4(G6PC1):c.809G>T (p.Gly270Val)

gnomAD frequency: 0.00002  dbSNP: rs80356483

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000239699	SCV000486040	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-03-18	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000239699	SCV000492901	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2015-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV000239699	SCV000829977	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2023-04-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). 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. ClinVar contains an entry for this variant (Variation ID: 21063). This missense change has been observed in individuals with glycogen storage disease (PMID: 7573034, 8733042, 10234610, 28397058, 28659124). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80356483, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the G6PC protein (p.Gly270Val).
Baylor Genetics	RCV000239699	SCV001163790	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000239699	SCV001478597	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2021-01-18	criteria provided, single submitter	clinical testing	Variant summary: G6PC c.809G>T (p.Gly270Val) 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 8e-06 in 251364 control chromosomes. c.809G>T has been widely reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1995, Chevalier-Porst_1996, Parvari_1999, Allegrini_2017, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete abolishment of Glucose 6-phosphatase activity and accumulation of glycogen in liver (example, Lei_1995, Chevalier-Porst_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001551101	SCV001771532	pathogenic	not provided	2020-04-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 10234610, 28659124, 7573034, 11739393, 28397058)
Revvity Omics, Revvity	RCV000239699	SCV002023773	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000239699	SCV002779285	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-04-21	criteria provided, single submitter	clinical testing
National Center for Biotechnology Information, National Institutes of Health	RCV000239699	SCV000298096	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-08-25	no assertion criteria provided	literature only
Natera, Inc.	RCV000239699	SCV002093325	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-03-17	no assertion criteria provided	clinical testing