Submissions for variant NM_000152.5(GAA):c.2432del (p.Leu811fs)

dbSNP: rs766560578

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208130	SCV001379505	pathogenic	Glycogen storage disease, type II	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 938833). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type II (PMID: 16433701, 18429042, 24269976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs766560578, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Leu811Argfs*37) 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).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001208130	SCV001422737	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Leu811ArgfsTer37 variant in GAA has been reported in at least 5 individuals with glycogen storage disease, segregated with disease in 2 affected relatives from 1 family (PMID: 25763511, 24269976, 16433701, 22252923, 18429042), and has been identified in 0.010% (1/9914) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766560578). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies have showed patients with the variant to be CRIM-negative (PMID: 25763511, 22252923). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 811 and leads to a premature termination codon 37 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. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease based on null GAA enzyme activity in lymphocytes, consistent with disease (PMID: 16433701). Additionally, the presence of this variant in combination with the reported pathogenic variant (p.Asp404Asn) and in an individual with glycogen storage disease increases the likelihood that the p.Leu811ArgfsTer37 variant is pathogenic (PMID: 22538254, 29122469, 29205646, 25687635, 22658377, 23787031, 26497565, 16433701, 243843240). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on the prediction that it causes loss of function, and its presence in combination with another pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001208130	SCV002556139	pathogenic	Glycogen storage disease, type II	2022-06-24	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2432delT (p.Leu811ArgfsX37) 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 4e-06 in 247066 control chromosomes (gnomAD). c.2432delT has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), including at least two cases where it has been detected in trans with a pathogenic variant (e.g. Amartino_2006, Pittis_2008, Bali_2012, Fu_2014, Gupta_2020). These data indicate that the variant is very likely to be associated with disease. The variant is also commonly observed in CRIM-negative Pompe Disease patients, indicated by an absense of protein detected by western blot (e.g. Bali_2012, Gupta_2020). Three assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001208130	SCV002092141	pathogenic	Glycogen storage disease, type II	2021-02-16	no assertion criteria provided	clinical testing