ClinVar Genomic variation as it relates to human health

This variant, c.1827delC (p.Tyr609Terfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This is supported by the absence of cross reactive immunological material studies in cultured fibroblasts from a patient with the variant (PMID 22252923). The highest maximum population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00007181 in the European non-Finnish population. This meets the ClinGen LSD VCEP's threshold for PM2. This variant was found in compound heterozygosity with a unique pathogenic variant in GAA in two patients with Pompe disease who also meet the ClinGen LSD VCEP's specifications for PP4; one of these patients is compound heterozygous for p.Tyr609Terfs and c.2481+102_2646 + 31del, and the other is compound heterozygous for p.Tyr609Terfs and c.-32-13T>G (PMIDs 26693141, 30655185). Therefore, PP4 and PM3 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 (PMID 14695532, 30564623). There is a ClinVar entry for this variant (Variation ID: 188936, 2 star review status) with 3 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, PP4.

Variant summary: GAA c.1827delC (p.Tyr609X) 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 2.9e-05 in 244672 control chromosomes. c.1827delC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) or Limb-girdle muscular dystrophies (e.g. Hermans_2004, Kishnani_2019, Nallamilli_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Tyr609Ter variant in GAA has been reported in 2 individuals (including 1 Australian individual) with Glycogen Storage Disease II (PMID: 14695532, 26693141), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 188936). This variant has been identified in 0.0072% (9/125326) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781088002). 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 leads to a premature termination codon at position 609, 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. This variant has been seen in combination with a reported pathogenic variant (PMID: 26693141). The phenotype of an individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity consistent with disease (PMID: 26693141). 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 the presence of this variant in a patient with a severe deficiency in GAA activity. ACMG/AMP Criteria applied: PVS1, PP4, PM2 (Richards 2015).

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 13 of 20). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other variants also predicted to undergo NMD, have been reported in patients with glycogen storage disease type II (Pombe disease). Patients homozygous for NMD-predicted truncating variants tend to be more severely affected (Decipher, PMID: 14695532). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and in several patients with Pombe disease (ClinVar, LOVD, PMID: 14695532, PMID: 26693141). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This sequence change creates a premature translational stop signal (p.Tyr609*) 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 (rs781088002, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 12897283, 14695532, 24269976). ClinVar contains an entry for this variant (Variation ID: 188936). For these reasons, this variant has been classified as Pathogenic.

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23891399, 30564623, 31086307, 30655185, 29122469, 26693141, 22252923, SavilleJT2021[Case-report], 35948506, 37701327, 34357340, 12897283, 24269976, 14695533, 38313679, 14695532)