Submissions for variant NM_000152.5(GAA):c.1537G>A (p.Asp513Asn)

gnomAD frequency: 0.00001  dbSNP: rs748047271

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001233657	SCV004042615	likely pathogenic	Glycogen storage disease, type II	2023-07-18	reviewed by expert panel	curation	The NM_000152.5: c.1537G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 513 (p.Asp513Asn). This variant has been detected in at least five individuals with Pompe disease. One patient of late-onset Pompe disease had documented GAA deficiency as 8.7% of the normal control level of GAA activity (PMID 33301762). Three siblings from one family had documented reduced GAA enzyme activity within the deficient range (clinical laboratory data). Patient(s) with this variant had documented in a Pompe Registry with the onset of symptoms less than 12 years of age (PMID 31342611). (PP4_Moderate). Of those individuals, one individual was homozygous for the variant, and three siblings were compound heterozygous for the variant and the pathogenic c.-32-13T>G variant (PM3 2.0 points, PMID 33301762, clinical laboratory data) (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006533 (2/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact on GAA function (PP3). Another missense variant c.1538A>G (p.Asp513Gly) (PMID 31510962, 33560568; ClinVar Variation ID: 638014) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 960182). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PP4_Moderate, PM3_Strong, PM2_Supporting, PP3, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023).
Invitae	RCV001233657	SCV001406261	pathogenic	Glycogen storage disease, type II	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 513 of the GAA protein (p.Asp513Asn). This variant is present in population databases (rs748047271, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 33301762). ClinVar contains an entry for this variant (Variation ID: 960182). 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%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507902	SCV001713738	likely pathogenic	not provided	2020-07-08	criteria provided, single submitter	clinical testing	PM2, PM5, PS3, PP3
Genome-Nilou Lab	RCV001233657	SCV001810610	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing