Submissions for variant NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)

gnomAD frequency: 0.00003  dbSNP: rs144016984

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001049848	SCV005089710	pathogenic	Glycogen storage disease, type II	2024-06-06	reviewed by expert panel	curation	The NM_000152.5:c.2297A>G variant in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 766 (p.Tyr766Cys. At least five patients diagnosed with Pompe disease, all late onset symptoms, have been reported with this variant. Three of these patients have documented laboratory values showing deficiency GAA activity (PMID: 29124014, 35071497, 37087815) (PP4_Moderate). Four patients are compound heterozygous for the variant and another variant that has been classified as pathogenic by the ClinGen LD VCEP, all phase unconfirmed, including c.2481+110_2646+39del (ClinVar Variation ID: 657307) (PMID: 37087815, 0.5 points), c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 35071497, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 30564623, 0.5 points), and c.1309C>T (p.Arg437Cys) (ClinVar Variation ID: 189082, SCV002540662.1) (PMID: 29124014, 0.5 points). Total 2 points (PM3_Strong). Another patient is reported with variant c.2297A>G (p.Tyr765Cys), which presumably is a typo for the amino acid number but cannot be confirmed (PMIDs: 21605996, 22676651). Another individual was identified by newborn screen, compound heterozygous for c.-32-13T>G (PMID: 33073003) but is not yet symptomatic, so was not included. One patient is compound heterozygous for the variant and c.1879_1881delTCC (p.Ser627del) ((PMID: 35071497), The allelic data from this patient will be used in the assessment of p.Ser627del and is not included here to avoid circular logic. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006534 (2/30610 alleles) in the South Asian population. In gnomAD v4.1, the highest MAF is 0.00002227 (1/44894 alleles) in the East Asian population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another amino acid change at the same position, c.2297A>C (p.Tyr766Ser)(ClinVar Variation ID: 420102), has been classified as pathogenic based on the specifications of the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 285197). 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 Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049848	SCV001213921	pathogenic	Glycogen storage disease, type II	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 766 of the GAA protein (p.Tyr766Cys). This variant is present in population databases (rs144016984, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21605996, 22538254, 30564623). ClinVar contains an entry for this variant (Variation ID: 285197). 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 with a positive predictive value of 95%. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 22538254, 28394184), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001049848	SCV001422964	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Tyr766Cys variant in GAA has been reported in at least two individuals with glycogen storage disease II (PMID: 22676651, 21605996, 29124014) and has been identified in 0.007% (2/30610) of South Asian chromosomes and 0.004% (5/128266) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144016984). 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 has also been reported in ClinVar (VariationID: 285197) as a VUS by EGL Genetics Diagnostics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr766Ser, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 420102). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 22676651, 21605996, 29124014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported likely pathogenic variants c.1561G>A (VariationID: 4022; PMID: 22676651, 21605996) and p.Arg437Cys (VariationID:189082, PMID: 29124014) and in individuals with glycogen storage disease II increases the likelihood that the p.Tyr766Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM5_supporting, PP4, PM3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001049848	SCV001442688	likely pathogenic	Glycogen storage disease, type II	2020-10-13	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2297A>G (p.Tyr766Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 250124 control chromosomes (gnomAD). c.2297A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. El-Gharbawy_2011, Herzog_2012, Fukuhara_2018, Nallamilli_2018). These data indicate that the variant may be associated with disease. Experimental evidence indicated GAA activity to be <10% in compound heterozygous patients with the variant (El-Gharbawy_2011, Herzog_2012, Fukuhara_2018). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and two ClinVar submitters (evaluation after 2014) cite it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000403113	SCV001796063	likely pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 33301762, 22676651, 30564623, 29124014, 33073003, 22538254, 35071497, 21605996, 37087815)
Genome-Nilou Lab	RCV001049848	SCV001810186	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000403113	SCV002025201	likely pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001049848	SCV004195437	pathogenic	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000403113	SCV000338123	uncertain significance	not provided	2016-01-04	flagged submission	clinical testing