Submissions for variant NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser)

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	RCV001065031	SCV002540647	pathogenic	Glycogen storage disease, type II	2022-06-03	reviewed by expert panel	curation	The NM_000152.5: c.2297A>C variant in GAA is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 766 (p.Tyr766Ser). At least 12 patients with this variant have been reported including 7 with documented GAA deficiency with <1% of normal mean control level of GAA activity in cultured fibroblasts or GAA activity in the affected leukocytes or dried blood spot (PMID: 22538254, 22521436, 31875618, Clinical Laboratory data), one noted to have deficient GAA activity but results were not provided (PMID: 28394184), and two reported to have Pompe disease with no further details (PMID: 26693141). At least three of these patients are receiving enzyme replacement therapy (PMID: 22521436, 22538254, 26693141 29289479, 30214072, 31899940) (PP4_Moderate). Of the reported patients, at least three are homozygous (PMID: 22521436, 22538254, 26693141 29289479, 31899940, Clinical Laboratory data, and seven were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP including c.1309C>T (p.Arg437Cys) (PMID: 22521436), c.-32-13T>G (Clinical Laboratory Data), c.2608C>T (p.Arg870Ter) (Clinical Laboratory Data), c.525delT (PMID: 30214072), all phase unknown, and c.1822C>T (p.Arg608Ter), confirmed in trans by parental testing (PMID: 31875618) (PM3_Very Strong). Two other individuals are compound heterozygous for the variant and either c.1118T>G (p.Leu373Arg) (Clinical Laboratory data) or c.2105G>A (p.Arg702His) (PMID: 28394184) but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005441 (1/18378 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.98 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies for this variant have not been published. Two other missense variants, c.2297A>G (p.Tyr766Cys) and 2296T>A (p.Tyr766Asn), in the same codon have been reported in patients with Pompe disease. The classification of c.2297A>C (p.Tyr766Ser) will be used to apply PM5 for those other variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 420102; 2 star review status) with five 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. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel: PM3_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022.
GeneDx	RCV000486923	SCV000568678	pathogenic	not provided	2023-08-11	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: 22538254, 21637107, 25139343, 31086307, 31875618, 28394184, 22521436, 26693141)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001065031	SCV001229969	pathogenic	Glycogen storage disease, type II	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 766 of the GAA protein (p.Tyr766Ser). This variant is present in population databases (rs144016984, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22521436, 22538254, 28394184; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 420102). 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: 21605996, 29124014), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001065031	SCV001339198	pathogenic	Glycogen storage disease, type II	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2297A>C (p.Tyr766Ser) results in a non-conservative amino acid change located in the glycosyl hydrolase family 31, C-terminal domain (IPR048395) 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 4e-06 in 250124 control chromosomes (gnomAD). c.2297A>C has been reported in the literature in multiple individuals affected with glycogen storage disease, type 2 (Pompe Disease) (examples: Yonee_2012, Bali_2015, Chen_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28394184, 26693141, 22521436). ClinVar contains an entry for this variant (Variation ID: 420102). Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001065031	SCV001423071	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Tyr766Ser variant in GAA has been reported in 6 individuals (including 1 Japanese individual and 1 Chinese individual) with Glycogen Storage Disease II (PMID: 26693141, 21637107, 22521436), and has also been reported pathogenic by GeneDx in ClinVar (Variation ID: 420102). This variant has been identified in 0.005% (1/18378) of East Asian 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. 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 presence of this variant in the homozygous state and in combination with a pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr766Ser variant is pathogenic (PMID: 22521436, 21637107). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity consistent with disease (PMID: 21637107, 22521436). One additional variant at the same position, p.Tyr766Cys, has been reported as a VUS in ClinVar (Variation ID: 285197). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000486923	SCV002021197	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001065031	SCV002779808	pathogenic	Glycogen storage disease, type II	2022-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001065031	SCV004195427	pathogenic	Glycogen storage disease, type II	2023-11-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001065031	SCV002092123	pathogenic	Glycogen storage disease, type II	2020-06-15	no assertion criteria provided	clinical testing