Submissions for variant NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)

dbSNP: rs1057516328

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000409827	SCV001443322	pathogenic	Glycogen storage disease, type II	2020-10-05	reviewed by expert panel	curation	This variant, c.2214G>A (p.Trp738Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, meeting PM2. An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). This data meets PM3_Supporting. In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). There is a ClinVar entry for this variant (Variation ID: 370223; 2 star review status) with two 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. ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Counsyl	RCV000409827	SCV000485477	likely pathogenic	Glycogen storage disease, type II	2015-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409827	SCV001211539	pathogenic	Glycogen storage disease, type II	2023-03-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp738*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 22676651). ClinVar contains an entry for this variant (Variation ID: 370223). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409827	SCV001422610	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp738Ter variant in GAA has been reported in 2 Chinese and 2 German individuals with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 21644219, 22676651), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370223). This variant has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516328). 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 738, 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 a pathogenic variant, and in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Trp738Ter variant is pathogenic (PMID: 22676651). The phenotype of an individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity less than 10% of WT, consistent with disease (PMID: 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 low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4, PM2 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409827	SCV002015051	pathogenic	Glycogen storage disease, type II	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2214G>A (p.Trp738X) 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 250908 control chromosomes. c.2214G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; Herzog_2012, Zheng_2011, Plockinger_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.