Submissions for variant NM_000152.5(GAA):c.1710C>G (p.Asn570Lys)

gnomAD frequency: 0.00002  dbSNP: rs765362308

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000670915	SCV002032125	likely pathogenic	Glycogen storage disease, type II	2021-12-02	reviewed by expert panel	curation	The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LSD VCEP threshold for PP3 (>0.7) and is higher than the LSD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. This variant was found in compound heterozygosity (phase unknown) with a pathogenic variant in GAA, c.2560C>T (p.Arg854Ter) in at least one patient with Pompe disease (PMID: 22538254, 22658377, 29122469, 31193175) and another patient with the pathogenic variant c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=)(PMID: 32248831) (PM3_Supporting). At least two individuals has been reported with this variant and GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay/ were reported to be on enzyme replacement therapy for Pompe disease (PMID: 17151339, 22538254, 29122469, 32248831)( PP4_Moderate). There is a ClinVar entry for this variant (Variation ID: 555153; 2 star review status) with 2 submitters classifying the variant as a VUS and 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PS3_Moderate, PM3_Supporting, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021).
Counsyl	RCV000670915	SCV000795831	uncertain significance	Glycogen storage disease, type II	2017-11-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670915	SCV001210924	pathogenic	Glycogen storage disease, type II	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 570 of the GAA protein (p.Asn570Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22658377, 29122469, 31086307). ClinVar contains an entry for this variant (Variation ID: 555153). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GAA function (PMID: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000670915	SCV001422538	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Asn570Lys variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 22658377, 18425781, 22538254) and has been identified in 0.011% (1/8702) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765362308). 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 as a VUS by Counsyl (VariationID: 555153). In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Asn570Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 17151339). Computational prediction tools do not provide strong support for or against an impact to the protein, but the Asn at position 570 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, the presence of this variant in combination with reported pathogenic variant p.Arg584Ter (VariationID: 4034, PMID: 29122469, 22658377, 22538254) and in an individual with glycogen storage disease II increases the likelihood that the p.Asn570Lys 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: PS3, PM2, PM3_Supporting PP4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670915	SCV001983410	likely pathogenic	Glycogen storage disease, type II	2021-09-22	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1710C>G (p.Asn570Lys) 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 251344 control chromosomes (gnomAD). c.1710C>G has been reported in combination with another GAA variant in the literature in individuals affected with infantile-onset Pompe disease or late-onset Pompe disease (Banugaria_2011, Kishnani_2019, Vanherpe_2020, De Groot_2021). These data indicate that the variant is likely to be associated with disease. At least one functional paper reports experimental evidence evaluating an impact on protein function and this variant results in reducing alpha-glucosidase activity in transfected cells compared to WT activity. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001784266	SCV002025223	likely pathogenic	not provided	2020-12-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670915	SCV004197894	likely pathogenic	Glycogen storage disease, type II	2024-02-23	criteria provided, single submitter	clinical testing