Submissions for variant NM_000152.5(GAA):c.871C>T (p.Leu291Phe)

gnomAD frequency: 0.00001  dbSNP: rs773417785

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001228970	SCV002032133	pathogenic	Glycogen storage disease, type II	2021-10-26	reviewed by expert panel	curation	The NM_000152.5:c.871C>T variant in GAA is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 291 (p.Leu291Phe). Five patients with Pompe disease and this variant have been reported, four with characteristics specific for Pompe disease including published laboratory values showing deficient GAA activity and/or on enzyme replacement therapy and/or with documented symptoms consistent with infantile onset Pompe disease (PMID 25526786, 30737479, 31086307, 32849613) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown, including c.716delT (PMID 32849613; 0.5 points), c.1798C>T (p.Arg600Cys)(PMID 26253708; 0.5 points), c.2238G>C (p.Trp746Cys)(PMID 25526786; 0.5 points), and c.2481+102_2646+31del (PMID 31086307; 0.5 points). One patient who is homozygous for the variant, due to uniparental disomy, has also been reported (PMID 30737479; 0.5 points). Total 2.5 points (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006378 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% wild type GAA activity and showed evidence of abnormal synthesis and processing on Western blot (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.701 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense changes, c.872T>C (p.Leu291Pro) and c.872T>A (p.Leu291His), at the same amino acid residue have been reported; c.872T>C (p.Leu291Pro) has been classified as pathogenic based on the specifications of the ClinGen LSD VCEP (CAID: CA401363854)(PM5). The data for this variant, c.871C>T (p.Leu291Phe, will be used in the assessment of p.Leu291His and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID 956209; 1 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PP3, PS3_Moderate, PM3_Strong, PM2_Supporting, PP4_Moderate. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021).
Invitae	RCV001228970	SCV001401400	pathogenic	Glycogen storage disease, type II	2023-04-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 956209). This variant disrupts the p.Leu291 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 25213570), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 25526786, 30737479, 31086307; Invitae). 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 (rs773417785, gnomAD 0.007%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 291 of the GAA protein (p.Leu291Phe). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001228970	SCV001422851	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Leu291Phe variant in GAA has been reported in 3 individuals with glycogen storage disease II (PMID: 30737479, 25526786, 18425781), and has been identified in 0.006% (1/15678) of African chromosomes and 0.006% (7/110146) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773417785). 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 using COS cells transfected with the variant provide some evidence that the p.Leu291Phe variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on the absence of any known pseudodeficiency alleles and GAA enzyme activity in lymphocytes being <10% of wild type, consistent with disease (PMID: 30737479). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Leu291Pro and p.Leu291His, have been reported in association with disease in the literature (PMID: 18458862, 22644586, 18425781). Additionally, the homozygous occurrence of this variant (PMID: 30737479), as well as the presence of this variant in combination with reported pathogenic variant p.Trp746Cys (VariationID: 265160; PMID 25526786), in individuals with glycogen storage disease II increases the likelihood that the p.Leu291Phe variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on in vitro functional studies, a patient with a phenotype highly specific for the disease, the presence of other pathogenic variants at the same location, and homozygous occurrence in an affected individual with another pathogenic variant. ACMG/AMP Criteria applied: PS3, PM2, PM3_supporting, PP4_moderate, PP3 (Richards 2015).
GeneDx	RCV001751444	SCV001986138	uncertain significance	not provided	2020-06-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18425781, 30737479, 31086307, 22644586, 30275481)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001228970	SCV002103372	pathogenic	Glycogen storage disease, type II	2022-02-21	criteria provided, single submitter	clinical testing	Variant summary: GAA c.871C>T (p.Leu291Phe) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245142 control chromosomes. c.871C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Kroos_2008, Liu_2014, Kishnani_2019, Labrijn-Marks_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal acid alpha-glucosidase activity (example, Kroos_2012). Three clinical diagnostic laboratories and an expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001228970	SCV002813046	likely pathogenic	Glycogen storage disease, type II	2022-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001751444	SCV003828430	uncertain significance	not provided	2019-01-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001228970	SCV004195489	pathogenic	Glycogen storage disease, type II	2023-09-11	criteria provided, single submitter	clinical testing