Submissions for variant NM_000151.4(G6PC1):c.648G>T (p.Leu216=)

gnomAD frequency: 0.00002  dbSNP: rs80356484

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723833	SCV000230857	pathogenic	not provided	2015-02-20	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000012783	SCV000267328	likely pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-03-18	criteria provided, single submitter	reference population
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012783	SCV000695640	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2016-11-23	criteria provided, single submitter	clinical testing	Variant summary: The G6PC c.648G>T (p.Leu216Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant may strengthen a cryptic 3' splicing acceptor site in exon 5. ESE finder predicts that this variant may create a novel SRp40 binding site. These predictions have been confirmed by at least one functional study (Kajihara_1995), showing this variant leads to a deletion of the front 91 nt of exon 5 in the patient's cDNA and this deletion results in a premature stop codon. This variant was found in 11/121428 control chromosomes at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported as the most common pathogenic variant in GSD1a patients in East Asia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000012783	SCV000915764	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2019-01-11	criteria provided, single submitter	clinical testing	The G6PC c.648G>T (p.Leu216Leu) synonymous variant is an established pathogenic variant that occurs in approximately 91% of Japanese glucogen storage disease type 1 (GSD1) alleles, 75% of Korean GSD1 alleles, and 54% of Chinese GSD1 alleles (Chou et al. 2008; Froissart et al. 2011; Bali 2013). Across a selection of available literature, the p.Leu216Leu variant has been reported in at least 55 individuals with glycogen storage disease type 1, including 47 in a homozygous state and eight in a compound heterozygous state (Kajihara et al. 1995; Akanuma et al. 2000). The p.Leu216Leu variant is reported at a frequency of 0.001271 in the East Asian population in the Exome Aggregation Consortium. The variant, although far from a splice junction, produces an aberrant transcript that eliminates 91 nucleotides and alters the reading frame, creating a premature termination at Tyr202 (Kajihara et al. 1995; Akanuma et al. 2000; Bali et al. 2013). Based on the collective evidence, the p.Leu216 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012783	SCV000942632	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change affects codon 216 of the G6PC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the G6PC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs80356484, gnomAD 0.1%). This variant has been observed in individual(s) with glycogen storage disease type 1 (PMID: 7668282, 10797430, 23000067, 23486339, 24980439; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g727t. ClinVar contains an entry for this variant (Variation ID: 12003). Studies have shown that this variant results in partial deletion of exon 5 and introduces a new termination codon (PMID: 7668282, 10748407). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000012783	SCV001163788	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-01-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000012783	SCV002023772	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2023-01-19	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000012783	SCV002318566	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-03-22	criteria provided, single submitter	clinical testing	Synonymous variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 7668282, PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012003, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000873). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 23000067, 11851840). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000723833	SCV002504154	pathogenic	not provided	2024-08-11	criteria provided, single submitter	clinical testing	Reported as a common pathogenic variant in association with GSD1a among individuals of Japanese, Korean, and Chinese backgrounds (PMID: 18449899); Published functional studies demonstrate this variant results in a deletion of 91 base pairs from exon 5 (PMID: 7668282, 10748407); Also known as G727T using alternate nomenclature; This variant is associated with the following publications: (PMID: 10797430, 24980439, 31109299, 32046761, 32924126, 10748407, 33763395, 36160031, 36452356, 36595986, 36167523, 35314707, 35257483, 35783312, 18449899, 37788110, 7668282)
Fulgent Genetics, Fulgent Genetics	RCV000012783	SCV002781326	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2022-03-18	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000012783	SCV005417841	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PM3_Strong+PP4+PP1_Moderate
OMIM	RCV000012783	SCV000033023	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2000-03-13	no assertion criteria provided	literature only
GeneReviews	RCV000012783	SCV000040461	not provided	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA		no assertion provided	literature only
Counsyl	RCV000012783	SCV001132194	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2014-01-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000012783	SCV002093318	pathogenic	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2017-03-17	no assertion criteria provided	clinical testing