Submissions for variant NM_000152.5(GAA):c.1465G>A (p.Asp489Asn)

dbSNP: rs398123169

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000173646	SCV003852732	pathogenic	Glycogen storage disease, type II	2023-02-07	reviewed by expert panel	curation	The NM_000152.5:c.1465G>A variant in GAA is a missense variant that is predicted to result in the substitution of aspartate by asparagine at amino acid 489 (p.Asp489Asn). This variant has been detected in at least 10 patients reported to have Pompe disease including 7 individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 17151339, 22081099, 22658377, 24395639, 24844452, 24923245, 29422078, 31193175), and three for whom GAA activity was not reported but who were treated by enzyme replacement (PMIDs: 25626711, 28574618). Nine individuals were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 16917947, 2208109, 24395639, 24844452, 24923245, 28574618), c.40_47del8 (PMID: 29422078), c.307T>G (p.Cys103Gly) (PMID: 18429042), c.1799G>A (p.Arg600His) (PMID: 22711147), c.2014C>T (p.Arg672Trp) (PMID: 16917947, 2208109), and another individual was compound heterozygous for the variant and c.2481+110_2646+39del (labeled as c.IVS17 + 102_IVS18 + 31 in the paper) confirmed in trans (PMID: 25626711). The variant was also detected in a parent of two affected children, now deceased, with c.1962_1964delAGA (p.Glu655del) in the other parent. However, as these variants were not confirmed to be present in the affected children, the data is not included (PMID: 22711147). Another individual was reported to have the variant but the cDNA sequence was not provided (PMID: 17616415 (PM3_VeryStrong). The highest population minor allele frequency in gnomAD is 0.00005 (1/21638) in the European Finnish population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In two different studies, this variant results in <2% GAA activity when expressed in COS-7 cells or Ad5-SV40 immortalized human GAA-deficient fibroblasts and, on Western blot, most of the gene product remained as the 110 kDa inactive precursor (PMID: 17915575, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.938 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 92465). 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 LSD VCEP (specifications version 2.0): PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).
Eurofins Ntd Llc (ga)	RCV000790665	SCV000224781	pathogenic	not provided	2013-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173646	SCV000695644	pathogenic	Glycogen storage disease, type II	2017-06-30	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.1465G>A (p.Asp489Asn) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120924 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple affected individuals and GAA activity testing confirm the variant results in deficiency. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl	RCV000173646	SCV000791020	likely pathogenic	Glycogen storage disease, type II	2017-04-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000173646	SCV000894161	likely pathogenic	Glycogen storage disease, type II	2021-10-10	criteria provided, single submitter	clinical testing
Invitae	RCV000173646	SCV001213830	pathogenic	Glycogen storage disease, type II	2023-08-03	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 489 of the GAA protein (p.Asp489Asn). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GAA function (PMID: 16917947). 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. ClinVar contains an entry for this variant (Variation ID: 92465). This missense change has been observed in individual(s) with glycogen storage disease type II (GSDII) (PMID: 16917947, 24844452, 29422078). 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 (rs398123169, gnomAD 0.004%).
CeGaT Center for Human Genetics Tuebingen	RCV000790665	SCV001245688	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000173646	SCV001423066	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Asp489Asn variant in GAA has been reported in 15 individuals (including 9 Italian, 1 Spanish, and 1 French individuals) with Glycogen Storage Disease II (PMID: 22081099, 17616415, 18429042, 22711147, 22658377, 24844452, 22980766, 25103075; DOI: 10.12032/TMRTH201804005), and has also been reported likely pathogenic by Counsyl and Fulgent Genetics and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 92465). This variant has been identified in 0.004621% (1/21638) of European (Finnish) chromosomes, 0.003% (1/30614) of South Asian chromosomes, and 0.001% (1/113488) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123169). 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 with COS cells transfected with this variant provide some evidence that the p.Asp489Asn variant may impact GAA activity (PMID: 19862843). 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 presence of this variant in combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp489Asn variant is pathogenic (PMID: 22658377, 22081099; 10.12032/TMRTH201804005). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected by assays with relevant tissue (PMID: 17151339, 22658377, 22081099, 17616415; DOI: 10.12032/TMRTH201804005). 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 with COS cells transfected with this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000790665	SCV003822651	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing