Submissions for variant NM_000152.5(GAA):c.258dup (p.Asn87fs)

dbSNP: rs761317813

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000291526	SCV002032142	pathogenic	Glycogen storage disease, type II	2021-09-28	reviewed by expert panel	curation	The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 10 patients with this variant and reported to have Pompe disease have been reported. This includes two patients with documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of them on enzyme replacement therapy (PMID 21484825, 31467850), a further 7, at least, patients on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831), and additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623). At least 7 patients are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA (PM3). Another two patients are compound heterozygous for the variant and either c.1195-8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282842, 2 star review status) with five submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific GAA criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.
Eurofins Ntd Llc (ga)	RCV000790707	SCV000334520	pathogenic	not provided	2015-08-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000291526	SCV000816240	pathogenic	Glycogen storage disease, type II	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn87Glnfs*9) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with glycogen storage disease II (PMID: 10206684, 16917947, 21484825). ClinVar contains an entry for this variant (Variation ID: 282842). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000291526	SCV001338289	pathogenic	Glycogen storage disease, type II	2020-02-09	criteria provided, single submitter	clinical testing	Variant summary: GAA c.258dupC (p.Asn87GlnfsX9) 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. The variant allele was found at a frequency of 1.2e-05 in 246016 control chromosomes. c.258dupC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Beesley_1998, Montalvo_2006, Bali_2011, Nallamilli_2018, Kishnani_2019). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000291526	SCV001422880	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Asn87GlnfsTer9 variant in GAA has been reported in 5 individuals (including 1 from the UK and 1 Italian individual) with Glycogen Storage Disease II (PMID: 16917947, 26873529, 21484825, 10206684), and has also been reported pathogenic by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 282842). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 87 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is a moderately established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Asn87GlnfsTer9 variant is pathogenic (PMID: 26873529). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with less than 5% of normal GAA activity detected in their fibroblasts (PMID: 21484825, 26873529). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on the predicted impact of the variant and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disorder II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000790707	SCV002021198	pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000291526	SCV002807224	pathogenic	Glycogen storage disease, type II	2021-11-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000291526	SCV004195446	pathogenic	Glycogen storage disease, type II	2023-11-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000291526	SCV001453579	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000790707	SCV001807617	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000790707	SCV001966803	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751421	SCV005362575	pathogenic	GAA-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The GAA c.258dupC variant is predicted to result in a frameshift and premature protein termination (p.Asn87Glnfs*9). This variant has been repeatedly reported in individuals with Pompe disease (see for example: Beesley et al. 1997. PubMed ID: 10206684; Nallamilli et al. 2018. PubMed ID: 30564623; Kishnani et al. 2019. PubMed ID: 31086307; Lee et al. 2019. PubMed ID: 31467850; Bali et al. 2011. PubMed ID: 21484825). Measured GAA activity for patients harboring this variant was demonstrated to be significantly decreased compared to normal (Bali et al. 2011. PubMed ID: 21484825; Lee et al. 2019. PubMed ID: 31467850). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD. Frameshift variants in GAA are expected to be pathogenic, and this variant has been interpreted as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/282842/). This variant is interpreted as pathogenic.