ClinVar Miner

Submissions for variant NM_000151.4(G6PC1):c.648G>T (p.Leu216=) (rs80356484)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Clinical Services Laboratory,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.
Invitae RCV000012783 SCV000942632 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2020-09-17 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. This variant is present in population databases (rs80356484, ExAC 0.1%). This variant has been observed to segregate with glycogen storage disease type 1 in a family (PMID: 7668282) and has been observed to be homozygous or in combination with another G6PC variant in individuals affected with this condition (PMID: 23000067, 23486339, 10797430, 24980439, Invitae). In one of these individuals the variant was observed on the opposite chromosome (in trans) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as g727t in the literature. ClinVar contains an entry for this variant (Variation ID: 12003). Experimental studies have shown that this variant disrupts splicing in vitro (PMID: 7668282, 10748407). 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 criteria provided, single submitter clinical testing
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 pathogenic Glycogen storage disease due to glucose-6-phosphatase deficiency type IA 2016-08-25 no assertion criteria 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

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