Submissions for variant NM_000152.5(GAA):c.3G>A (p.Met1Ile)

dbSNP: rs1187796945

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249078	SCV001423033	likely pathogenic	Glycogen storage disease, type II	2020-01-29	criteria provided, single submitter	curation	The c.3G>A (p.Met1?) variant in GAA has been reported in at least three individuals with glycogen storage disease (PMID: 21803581, 18425781, 22252923, 22981821), and has been identified in 0.001% (1/111790) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1187796945). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the first amino acid of exon two and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 122 and there are at least seven reported pathogenic or likely pathogenic variants in ClinVar between amino acid 1 and amino acid 122. Proteins lacking this region are predicted to be extremely unstable (PMID: 22252923, 30192042, 22644586), suggesting that the c.3G>A variant may result in a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. In vitro functional studies provide some evidence that the p.Met1? variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and ClinVar (PMID: 22252923, 30192042, 29889338, 28316933, 22644586; Variation ID: 188785). This variant was reported in combination with known pathogenic variants (VariationID: 4027, PMID: 22981821, 21803581, 22252923) and in individuals with glycogen storage disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249078	SCV001737739	likely pathogenic	Glycogen storage disease, type II	2021-06-12	criteria provided, single submitter	clinical testing	Variant summary: GAA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream putative in-frame start codon (Methionine) is located at p.Met122 in exon 2 of the GAA gene. The predicted truncated protein loses part of N-terminus of the encoded protein. Loss-of-function variants upstream of p.Met122 have been reported to be associated with Glycogen Storage Disease, Type 2 (example, p.R40*, p.Q115*, HGMD database). The variant allele was found at a frequency of 4e-06 in 247470 control chromosomes. c.3G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and has been subsequently cited by other studies due to authorship/institutional/patient overlap between studies (example, Kroos_2008, Yves Carlier_2011, Bali_2012, Desai_2019, Kishnani_2019, ElMallah_2020). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and the HGMD database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249078	SCV004297574	pathogenic	Glycogen storage disease, type II	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with Pompe disease (PMID: 22252923, 29124014, 29422078, 31086307). ClinVar contains an entry for this variant (Variation ID: 972816). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GAA function (PMID: 22644586, 31301153). For these reasons, this variant has been classified as Pathogenic.