Submissions for variant NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)

gnomAD frequency: 0.00001  dbSNP: rs1403885484

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001353145	SCV004227908	uncertain significance	Glycogen storage disease, type II	2023-12-20	reviewed by expert panel	curation	The NM_000152.5:c.2783A>G in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 928 (p.Tyr928Cys). The variant has been identified in at least four individuals (all Indian where the country of origin is known). One of these patients has symptoms consistent with late onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID: 33741225) (PP4_Moderate). Three individuals are homozygous for the variant (PMID: 33301762, clinical diagnostic laboratory), and one individual is compound heterozygous for the variant and a variant of uncertain significance, c.2015G>T (p.Arg672Leu) (PMID: 29122469, 33741225). The allelic data for this patient will be used in the classification of p.Arg672Leu and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00003294 (3/91080 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: : 1048589). In summary, this variant meets the criteria to be classified as a variant of unceratin significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023).
NxGen MDx	RCV001353145	SCV001547517	likely pathogenic	Glycogen storage disease, type II	2020-02-07	criteria provided, single submitter	clinical testing	This missense variant c.2783A>G (p.Tyr928Cys) in GAA exon 19 maintains a polar side chain however, it is not found in gnomAD exomes (PM2) and consensus from in silico predictions supports a disruptive effect (PP3). This variant was first reported in Bali et al. PMID 22252923 in 2 cases and has been reported in 7 additional cases in a South Indian Infant-Onset Pompe Disease cohort in Gupta et al. PMID 31606152. We interpret c.2783A>G to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001353145	SCV002112700	pathogenic	Glycogen storage disease, type II	2024-08-10	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 928 of the GAA protein (p.Tyr928Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 22252923, 29122469, 31606152, 33301762, 33741225). ClinVar contains an entry for this variant (Variation ID: 1048589). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003136020	SCV003828570	likely pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001353145	SCV004030051	pathogenic	Glycogen storage disease, type II	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2783A>G (p.Tyr928Cys) 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 was absent in 250516 control chromosomes. c.2783A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Example: Thomas_2021, Mori_2017). Additionally, the a-glucosidase activity in several homozygous patients is significantly reduced when compared to wildtype (Thomas_2021). 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: 29122469, 33301762). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV001353145	SCV004035128	likely pathogenic	Glycogen storage disease, type II	2023-09-17	criteria provided, single submitter	clinical testing	The homozygous mis-sense variant c.2783A>G (p.Tyr928Cys) has been identified in a group of patients presented with symptoms like respiratory distress, cardiomegaly, ventilator support, muscle weakness, hypotonia, protuberant abdomen, hepatomegaly and feeding difficulties. The age of onset of symptoms ranged from at birth to 6 months. This has been previously reported PMID: 31606152
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001353145	SCV005420547	likely pathogenic	Glycogen storage disease, type II	2024-10-04	criteria provided, single submitter	research	PM2,PP3,PM5,PP4,PM3(moderate)
Fulgent Genetics, Fulgent Genetics	RCV001353145	SCV005653259	pathogenic	Glycogen storage disease, type II	2024-05-29	criteria provided, single submitter	clinical testing