This variant, c.1548G>A (p.Trp516Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP's specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Therefore, PP4 and PM3_Strong can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). There is a ClinVar entry for this variant (Variation ID: 189025, 2 star review status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. 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: PVS1, PM2, PM3_Strong, PP4.

This nonsense variant found in exon 10 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with Glycogen storage disease II (PMID: 14695532, 29181627, 29122469, 24715333). Loss-of-function variation in GAA is an established mechanism of disease (PMID:18425781, 22252923). This variant has been observed in individuals with low alpha-glucosidase enzyme activity, suggestive of Glycogen storage disease II (PMID: 25243733, 22676651).The c.1548G>A (p.Trp516Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00007 (2/282510) and thus is presumed to be rare. Based on the available evidence, the c.1548G>A (p.Trp516Ter) variant is classified as a Pathogenic.

A known stop-gain variant, c.1548G>A p.(Trp516Ter) in exon 10 of GAA (Kishnani et al., 2019; Mori et al., 2017; VCV000189025.71) is observed in homozygous state in proband. Sanger validation and segregation analysis showed that the variant was observed in homozygous state in proband and heterozygous state in parents. This variant is observed in heterozygous state in 80 individuals and is not observed in homozygous state in gnomAD database (v4.1.0). This variant is not observed in homozygous and/or heterozygous state in our in-house data of 3840 exomes. This stop-gain variant introduces a premature stop codon which may either trigger nonsense-mediated mRNA decay or result in a truncated protein product

This sequence change creates a premature translational stop signal (p.Trp516*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs140826989, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Pompe disease and low alpha-glucosidase enzyme activity (PMID: 14695532, 22676651, 24715333, 25243733, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 189025). For these reasons, this variant has been classified as Pathogenic.

Variant summary: GAA c.1548G>A (p.Trp516X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes. c.1548G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- eg Hermans_2004, deVries_2010, Messinger_2012, Stepien_2016). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The GAA c.1548G>A (p.Trp516*) variant has been reported in at least three individuals affected by glycogen storage disease II (Pompe disease) who were compound heterozygous for this variant and a pathogenic or likely pathogenic variant, with one case confirmed in trans (Bergsma AJ et al., PMID: 25243733; Messinger YH et al., PMID: 22237443; de Vries JM et al., PMID: 20826098). This variant has been reported in the ClinVar database as a pathogenic variant by eighteen submitters, including an expert panel, and as likely pathogenic by one submitter (Variation ID: 189025; Goldstein JL et al., PMID: 37907381). This variant leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant is only observed on 1 out of 13,006 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Based on available information and the specific GAA-ACMG/AMP guidelines for variant interpretation (Goldstein JL et al., PMID: 37907381; Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

The c.1548G>A;p.(Trp516*) variant creates a premature translational stop signal in the GAA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 189025; PMID: 32317649; 30155607; 29181627; 29122469; 26873529) - PS4. The variant is present at low allele frequencies population databases (rs140826989 – gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp516*) was detected in trans with a pathogenic variant (PMID: 32317649; 29181627; 29122469; 26873529) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

The c.1548G>A sequence change results in the creation of a premature stop codon at amino acid residue 516, p.Trp516*. This sequence change is predicted to result in an abnormal, truncated GAA transcript that is likely to result in mRNA nonsense-mediated decay and no protein production. Loss of function is a known disease mechanism for Pompe disease. This pathogenic sequence change has previously been identified in the compound heterozygous state with other pathogenic variants in several individuals with Pompe disease (PMID: 20826098, 22237443, 25243733). This sequence change has been described in the gnomAD database with an overall population frequency of 0.0007%. Collectively, this evidence indicates that this sequence change is pathogenic.

The c.1548G>A variant in GAA is a nonsense variant predicted to introduce a stop codon at amino acid 516. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 20826098, 26497565, 24715333). Given the available evidence, this variant is classified as Pathogenic.

The p.Trp516Ter variant in GAA has been reported in at least 16 individuals (including at least 10 Caucasian individuals) with Glycogen Storage Disease II (PMID: 22676651, 25155446, 14695532, 17027861, 15048888, 18757064, 20826098, 22237443, 25243733, 24715333, 22252923, 26873529, 23601496), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189025). This variant has been identified in 0.002% (2/128904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140826989). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with 3 pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp516Ter variant is pathogenic (PMID: 20826098, 25243733, 22237443, 22676651; Variation ID: 4031, 4033). The phenotype of six individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity within fibroblasts or a dried blood spot (PMID: 20826098, 23601496, 22237443, 25243733, 26873529, 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2, PP4 (Richards 2015).

Reported in multiple unrelated patients with glycogen storage disease type II (GSDII) (Hermans et al. 2004; van et al. 2015; Elder et al. 2013; Bergsma et al. 2015; de Vries JM et al. 2010); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22252923, 18757064, 34134972, 31965297, 32888769, 31086307, 25525159, 25155446, 29181627, 25541616, 22676651, 24715333, 20826098, 23601496, 15048888, 25243733, 14695532)

The GAA c.1548G>A variant is predicted to result in premature protein termination (p.Trp516*). This variant has been reported in multiple unrelated patients with glycogen storage disease type II (GSDII) together with another pathogenic variant in GAA (see example: Hermans et al. 2004. PubMed ID: 14695532; Löscher et al. 2018. PubMed ID: 29181627). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in GAA are expected to be pathogenic. This variant is interpreted as pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.