Submissions for variant NM_000152.5(GAA):c.1437+1G>A

dbSNP: rs1555600575

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000671773	SCV004227900	likely pathogenic	Glycogen storage disease, type II	2023-05-16	reviewed by expert panel	curation	This variant, c.1437+1G>A, alters the donor splice site of intron 9. Based on RT-PCR results from a patient who is compound heterozygous for the variant, this results in skipping of exon 9, which leads to an in frame deletion of p.Asp443_Lys479del (PMID 22676651), including part of the GAA catalytic barrel (PMID 22253258). Western blot analysis of protein extracted from cultured skin fibroblasts from a patient who is homozygous for the variant revealed that the patient was positive from cross-reactive immunological material, supporting that the variant results in an in-frame consequence (PMID 22252923). Based on these results, PVS1_Strong was applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2_Supporting. Two patients with Pompe disease have been reported who are homozygous for the variant and meet the ClinGen LSD VCEP's PP4 specifications (PMID 22555271, 22252923; personal communication), meeting PM3 and PP4_Moderate. Another patient has been reported with the variant in trans with c.1076-22G>A (PMID 22676651). In trans data from this patient will be used in the assessment of c.1076-22G>A and is not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 555864; two star review status) with five submitters classifying the variant as pathogenic and one submitter classifying as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Moderate.
Counsyl	RCV000671773	SCV000796792	pathogenic	Glycogen storage disease, type II	2017-12-29	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000671773	SCV001422700	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1437+1G>A variang in GAA has been reported in 4 individuals with glycogen storage disease II (PMID: 22555271, 28266734, 22676651, 22252923) and has been reported in ClinVar as pathogenic by Counsyl (VariationID: 555864). This variant has been identified in 0.003% (1/34538) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1555600575). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using an expression vector system demonstrating abnormal splicing provide some evidence that the c.1437+1G>A variant may impact protein function (PMID: 11343339). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause skipping of exon 9 leading to an absent protein (PMID: 22676651, 22252923, 11343339). Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000671773	SCV001572521	pathogenic	Glycogen storage disease, type II	2021-04-10	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1437+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248246 control chromosomes. c.1437+1G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Reuser_2019). 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. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001592852	SCV001824018	pathogenic	not provided	2020-08-18	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28266734, 22676651, 22555271, 22252923, 23430949)
Revvity Omics, Revvity	RCV001592852	SCV002021187	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV000671773	SCV002175462	pathogenic	Glycogen storage disease, type II	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Pompe disease (PMID: 11343339, 18429042, 22252923). ClinVar contains an entry for this variant (Variation ID: 555864). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000671773	SCV004197858	pathogenic	Glycogen storage disease, type II	2023-03-10	criteria provided, single submitter	clinical testing