Submissions for variant NM_000152.5(GAA):c.2242dup (p.Glu748fs)

dbSNP: rs777275355

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000411023	SCV001371704	pathogenic	Glycogen storage disease, type II	2020-05-04	reviewed by expert panel	curation	This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4.
GeneDx	RCV000524025	SCV000617645	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Reported in multiple patients with GSDII in published literature, including at least one patient who had biochemical testing that was diagnostic and consistent with the results seen in other patients with pathogenic variants in this gene (PMID: 10206684, 16917947, 21484825); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17915575, 29122469, 26873529, 31254424, 34501319, 10206684, 16917947, 22644586, 9535769, 36046397, 21484825)
Eurofins Ntd Llc (ga)	RCV000524025	SCV000706065	pathogenic	not provided	2017-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411023	SCV000959782	pathogenic	Glycogen storage disease, type II	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu748Glyfs*48) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs777275355, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469). This variant is also known as insGnt2243 and insG2242. ClinVar contains an entry for this variant (Variation ID: 370651). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000411023	SCV001423057	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Glu748GlyfsTer48 variant in GAA has been reported in at least 5 individuals (including 2 from the UK, and 1 Italian individuals) with Glycogen Storage Disease II (PMID: 16917947, 9535769, 10206684, 21484825), and has also been reported likely pathogenic by Counsyl and pathogenic by GeneDx and EGL in ClinVar (Variation ID: 370651). This variant has been identified in 0.0018% (2/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516659). 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 predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 748 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with at least 2 pathogenic variants curated by our study and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu748GlyfsTer48 variant is pathogenic (PMID: 9535769, 29122469). The phenotype of two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in fibroblasts (PMID: 9535769, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000524025	SCV002023879	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411023	SCV002051378	pathogenic	Glycogen storage disease, type II	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2242dupG (p.Glu748GlyfsX48) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.2501_2502delCA|p.Thr834ArgfsX49; c.2544delC|p.Lys849ArgfsX38). The variant allele was found at a frequency of 8e-06 in 250780 control chromosomes. c.2242dupG has been reported in the literature in multiple individuals affected with both infantile (example: Beesley_1998, Huie_1998) and late/adult (example: Montalvo_2006, Stepien_2016) onset forms of Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function: fibroblasts cultured from a patient with the variant of interest alongside a null variant showed <0.1% normal enzymatic activity (Huie_1998). Eight ClinVar submitters, including one expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have assessed the variant since 2014: seven have classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000411023	SCV004195506	pathogenic	Glycogen storage disease, type II	2024-03-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000411023	SCV000486019	likely pathogenic	Glycogen storage disease, type II	2016-03-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411023	SCV001459752	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing