Submissions for variant NM_000152.5(GAA):c.2512C>T (p.Gln838Ter)

gnomAD frequency: 0.00001  dbSNP: rs369532274

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001200861	SCV001371718	pathogenic	Glycogen storage disease, type II	2020-05-04	reviewed by expert panel	curation	This variant, c.2512C>T (p.Gln838Ter), 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 0.00006 in the African population, meeting PM2. It has been reported in two siblings with infantile onset Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4, and who are compound heterozygous for the variant and c.2105G>T (p.Arg702Leu) (PMID 26167453). However, this in trans data will be used in the assessment of p.Arg702Leu and is not included here in order to avoid a circular argument. Another patient, with limb girdle muscular dystrophy, has been reported to be compound heterozygous for the variant and c.-32-13T>G. However, residual GAA activity was not provided, and therefore this data was not included (PMID 30564623). There is a ClinVar entry for this variant (Variation ID: 92479, 1 star review status) with one submitter classifying the variant as 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, PP4.
Eurofins Ntd Llc (ga)	RCV000175263	SCV000226720	pathogenic	not provided	2016-09-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001200861	SCV001422608	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gln838Ter variant in GAA has been reported in 2 African American individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 26167453), and has also been reported pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 92479). This variant has been identified in 0.006% (1/16188) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369532274). 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 838, 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 reported in trans with a reported likely pathogenic variant and in 2 individuals with Glycogen Storage Disease II (PMID: 26167453; Variation ID: 92472). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in fibroblasts or muscle tissue (PMID: 26167453). 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 occurrences with a reported likely pathogenic GAA variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000175263	SCV002023823	pathogenic	not provided	2021-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200861	SCV002118402	pathogenic	Glycogen storage disease, type II	2023-06-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 92479). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 29122469, 31342611). This variant is present in population databases (rs369532274, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Gln838*) 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).
Fulgent Genetics, Fulgent Genetics	RCV001200861	SCV002813193	pathogenic	Glycogen storage disease, type II	2021-09-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001200861	SCV005058739	pathogenic	Glycogen storage disease, type II	2024-02-22	criteria provided, single submitter	clinical testing