Submissions for variant NM_000152.5(GAA):c.1195-15G>A

gnomAD frequency: 0.00006  dbSNP: rs373840229

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000287500	SCV000407277	uncertain significance	Glycogen storage disease, type II	2018-01-12	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	RCV000419694	SCV000527907	likely benign	not specified	2017-09-26	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000419694	SCV000917397	uncertain significance	not specified	2021-07-02	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1195-15G>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. 4/4 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 0.00021 in 248530 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than the maximum expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.0042), allowing no conclusion about variant significance. c.1195-15G>A has been reported in the literature in at least one individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Muller-Felber_2007, Schoser_2007, Lim_2015). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000287500	SCV001422875	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous c.1195-15G>A variant in GAA has been reported in 1 individual in Germany with Glycogen Storage Disease II (PMID: 17643989), and has been reported as a VUS by Illumina and Integrated Genetics and a likely benign variant by GeneDx in ClinVar (Variation ID: 325786). This variant has been identified in 0.263% (27/10254) of Ashkenazi Jewish chromosomes, including 1 homozygote, and 0.014% (5/35320) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373840229). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015).
Invitae	RCV000287500	SCV001618751	likely benign	Glycogen storage disease, type II	2024-01-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003912357	SCV004735639	likely benign	GAA-related condition	2021-10-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).