Submissions for variant NM_000151.4(G6PC1):c.969C>A (p.Tyr323Ter)

dbSNP: rs780226142

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169104	SCV000220300	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2014-05-08	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000726277	SCV000343386	pathogenic	not provided	2016-06-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169104	SCV001163791	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	RCV000169104	SCV001363567	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-10-25	criteria provided, single submitter	clinical testing	Variant summary: G6PC c.969C>A (p.Tyr323X) 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 associated with Glycogen Storage Disease in HGMD. The variant was absent in 251410 control chromosomes. c.969C>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease Type Ia (Calderaro_2013 and Sperb-Ludwig_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Studies using G6PC-EGFP construct shows undetectable level of protein expression and significantly altered N-linked glycosylatin (Plona_2019) . Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169104	SCV001406031	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr323*) in the G6PC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the G6PC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 23046672). ClinVar contains an entry for this variant (Variation ID: 188777). This variant disrupts a region of the G6PC protein in which other variant(s) (p.Gln347*) have been determined to be pathogenic (PMID: 7573034, 8182131, 8733042, 10070617, 11949931, 28397058). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169104	SCV002811000	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-04-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726277	SCV004228180	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	PM2, PM3_supporting, PS3, PVS1_strong
GeneDx	RCV000726277	SCV005327149	pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Reported in a patient in the published literature with glycogen storage disease type 1 (PMID: 23046672); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 35 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate a damaging effect on protein expression (PMID: 34258141); This variant is associated with the following publications: (PMID: 10070617, 11949931, 31508908, 8182131, 7573034, 8733042, 28397058, 23046672, 34258141)