Submissions for variant NM_000151.4(G6PC1):c.340+10C>A

gnomAD frequency: 0.00124  dbSNP: rs368450665

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725686	SCV000338595	uncertain significance	not provided	2016-01-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082635	SCV000402978	uncertain significance	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000371551	SCV000513086	likely benign	not specified	2017-06-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001082635	SCV001107623	likely benign	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA	2024-01-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000371551	SCV001362495	benign	not specified	2019-12-13	criteria provided, single submitter	clinical testing	Variant summary: G6PC c.340+10C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00096 in 251376 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.039 fold of the estimated maximal expected allele frequency for a pathogenic variant in G6PC causing Glycogen Storage Disease Type Ia phenotype (0.0017), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.340+10C>A has been reported in the literature in an individual affected with Glycogen Storage Disease Type Ia (Mahmoud_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant twice as uncertain significance and onces as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Natera, Inc.	RCV001274703	SCV001459072	likely benign	Glycogen storage disease, type I	2020-05-30	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000371551	SCV001926466	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725686	SCV001971083	likely benign	not provided		no assertion criteria provided	clinical testing