Submissions for variant NM_000152.5(GAA):c.2331+2T>A

gnomAD frequency: 0.00001  dbSNP: rs1057517148

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411608	SCV000486824	pathogenic	Glycogen storage disease, type II	2016-08-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000411608	SCV001423063	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.2331+2T>A variant in GAA has been reported in at least 4 individuals (including 1 Belgian individual) with Glycogen Storage Disease II (PMID: 22252923, 18425781, 20817528), and has also been reported pathogenic by Counsyl in ClinVar (Variation ID: 371281). This variant has been identified in 0.001% (1/111712) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057517148). 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 occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal 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 an individual with Glycogen Storage Disease II slightly increases the likelihood that the c.2331+2T>A variant is pathogenic (PMID: 20817528). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their fibroblasts (PMID: 20817528). 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 an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001702635	SCV002021202	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411608	SCV004197787	pathogenic	Glycogen storage disease, type II	2024-02-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411608	SCV004296886	pathogenic	Glycogen storage disease, type II	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371281). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 31086307, 32071926). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 16 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702635	SCV001927197	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702635	SCV001973856	pathogenic	not provided		no assertion criteria provided	clinical testing