Submissions for variant NM_000152.5(GAA):c.1411_1414del (p.Glu471fs)

gnomAD frequency: 0.00001  dbSNP: rs770276275

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169228	SCV001443324	pathogenic	Glycogen storage disease, type II	2020-10-08	reviewed by expert panel	curation	This variant, c.1411_1414del (p.Glu471ProfsTer5), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002513 in the East Asian population, meeting PM2. This variant has been reported multiple times in Asian patients with Pompe disease presenting clinically and identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu) (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). There is a ClinVar entry for this variant (Variation ID: 188874, 2 star review status) with three submitters classifying the variant as 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.
Counsyl	RCV000169228	SCV000220494	likely pathogenic	Glycogen storage disease, type II	2014-07-09	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169228	SCV001209354	pathogenic	Glycogen storage disease, type II	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu471Profs*5) 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 (rs770276275, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with infantile-onset Pompe disease (PMID: 8604985, 18458862, 28394184, 29046207). ClinVar contains an entry for this variant (Variation ID: 188874). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169228	SCV001362547	pathogenic	Glycogen storage disease, type II	2019-10-24	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1411_1414delGAGA (p.Glu471ProfsX5) 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. The variant allele was found at a frequency of 1.6e-05 in 249358 control chromosomes (gnomAD). c.1411_1414delGAGA has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). The variant has predominantly associated with infantile onset of the disease (e.g. Chien_2006, Labrousse_2010, Shieh_1996, Wan_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169228	SCV001423056	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Glu471ProfsTer5 variant in GAA has been reported in 13 individuals from China or Taiwan with Glycogen Storage Disease II (PMID: 28394184, 18458862, 19948615, 10338092, 8604985), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 188874). This variant has been identified in 0.025% (5/19900) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770276275). 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 471 and leads to a premature termination codon 5 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 reported pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu471ProfsTer5 variant is pathogenic (PMID: 18458862, 19948615, 28394184; Variation ID: 189006, 4029). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected by assays with patient fibroblasts and/or lymphocytes (PMID: 18458862, 19948615, 28394184). 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	RCV001781522	SCV002023793	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169228	SCV002793115	pathogenic	Glycogen storage disease, type II	2022-03-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169228	SCV004197862	pathogenic	Glycogen storage disease, type II	2023-03-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169228	SCV001455615	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751315	SCV005354511	pathogenic	GAA-related disorder	2024-06-19	no assertion criteria provided	clinical testing	The GAA c.1411_1414delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu471Profs*5). This variant has been reported as compound heterozygous variant in individuals with glycogen storage disease type 2 (GSD II), also known as Pompe disease (Ko et al. 1999. PubMed ID: 10338092; Mori et al. 2017. PubMed ID: 29122469; Chien et al. 2014. PubMed ID: 25466677; Labrousse et al. 2009. PubMed ID: 20080426; Chen et al. 2017. PubMed ID: 28394184). Biochemical studies revealed significantly reduced GAA enzyme activity in individuals with the c.1411_1414del variant (Wan et al. 2008. PubMed ID: 18458862; Labrousse et al. 2009. PubMed ID: 20080426). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD. Of note, this variant has been reported to be in cis with the c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) haplotype (Labrousse et al. 2009. PubMed ID: 20080426; Chien et al. 2014. PubMed ID: 25466677; Mori et al. 2017. PubMed ID: 29122469). The c.1411_1414delGAGA variant has been classified as likely pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (LSD VCEP), as well as pathogenic or likely pathogenic by other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/). We interpret this variant as pathogenic.