Submissions for variant NM_000152.5(GAA):c.1856G>A (p.Ser619Asn)

gnomAD frequency: 0.00001  dbSNP: rs753269119

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409055	SCV000485388	likely pathogenic	Glycogen storage disease, type II	2015-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409055	SCV001361531	pathogenic	Glycogen storage disease, type II	2019-01-10	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1856G>A (p.Ser619Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 237486 control chromosomes (gnomAD). The variant, c.1856G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2006, Remiche_2014, Gallardo_2011, Parenti_2014, Arslan_2016). One patient, Arslan_2016, was found to be homozygous for two deleterious variants, the variant of interest and c.32-13T>G, to which the authors indicate the phenotype was more progressive. The patient was born to consanguineous Turkish parents. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of residual acid -glucosidase activity (Kroos_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409055	SCV001409389	pathogenic	Glycogen storage disease, type II	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 619 of the GAA protein (p.Ser619Asn). This variant is present in population databases (rs753269119, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 16838077, 22990675, 24158270, 25998610, 26946079). ClinVar contains an entry for this variant (Variation ID: 370146). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14643388, 21471980, 25213570, 27363342, 29124014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409055	SCV001422906	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). This variant has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370146) and has been identified in 0.013% (4/29974) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753269119). 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 provide some evidence that the p.Ser619Asn variant may impact proteolytic activation of GAA and GAA activity (PMID: 16838077, 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. One pathogenic additional variant at the the same position, p.Ser619Arg, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 550825). The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser619Asn variant is pathogenic (PMID: 16838077). Of note, this variant has also been observed in cis with the known pathogenic variant c.-32-13T>G with both variants in the homozygous state in an individual with Glycogen Storage Disorder II (PMID: 26946079). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 24158270, 26946079, 16838077). 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, another pathogenic variant at the same position, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM3_Supporting, PP4 (Richards 2015).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814152	SCV001755320	likely pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001726152	SCV001961733	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001726152	SCV002025204	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000409055	SCV002780847	pathogenic	Glycogen storage disease, type II	2022-02-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409055	SCV004197802	pathogenic	Glycogen storage disease, type II	2023-07-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000409055	SCV004848817	pathogenic	Glycogen storage disease, type II	2022-11-03	criteria provided, single submitter	clinical testing	The p.Ser619Asn variant in GAA has been reported in at least 8 individuals (6 in the compound heterozygous state) with Glycogen Storage Disease II. Of note, in 2 of these individuals (one homozygote and one compound heterozygote), this variant was in cis with the known pathogenic variant c.-32-13T>G (Gallardo 2011 PMID: 22194990, Arslan 2016 PMID: 26946079, Alejaldre 2012 PMID: 22980766, Kroos 2006 PMID: 16838077, Remiche 2014 PMID: 24158270, Parenti 2014 PMID: 25052852, Fecarotta 2013 PMID: 23668440, Gutiérrez-Rivas 2015 PMID: 25998610). This variant has also been reported in ClinVar (Variation ID: 370146) and has been identified in 2/4830 of South Asian and 1/67968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using patient tissues provide some evidence that this variant may impact proteolytic activation of GAA and GAA activity (Kroos 2006 PMID: 16838077). 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. Another variant involving this codon (p.Ser619Arg) has been identified in individuals with autosomal recessive Glycogen Storage Disease II and is classified as likely pathogenic/pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM5, PP3, PM3_Very strong.
GeneDx	RCV001726152	SCV005325574	pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced total enzyme amount and in vitro enzyme activity (PMID: 16838077); 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: 34530085, 31589614, 33202836, 23668440, 16838077, 26946079, 31086307, 21471980, 25052852, 14643388, 19862843, 22194990, 22980766, 22990675, 27363342, 25213570, 25998610, 33073007, 29124014, 24158270)
Natera, Inc.	RCV000409055	SCV002092071	pathogenic	Glycogen storage disease, type II	2020-04-10	no assertion criteria provided	clinical testing