Submissions for variant NM_000152.5(GAA):c.2799+4A>G

gnomAD frequency: 0.00003  dbSNP: rs778032599

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000674123	SCV004042617	likely pathogenic	Glycogen storage disease, type II	2023-06-27	reviewed by expert panel	curation	The NM_000152.5:c.2799+4A>G is located in the donor splice site region of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.62 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). Two individuals with Pompe disease have been reported to have this variant; one has documentation of deficient GAA activity and is on enzyme replacement therapy (PMID: 26873529) (PP4_Moderate), and the second patient has limb girdle muscular dystrophy (PMID: 30564623). Both individuals are compound heterozygous for this variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.1548G>A (p.Trp516Ter) (PMID: 26873529) or c.2501_2502delCA (PMID: 30564623); the phase is unknown in each case (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16172 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additional variants in this splice region have been identified, including c.2799+2C>T, c.2799+2C>A, and c.2799+5G>A (PMID: 28265479); all currently classified by the ClinGen LD VCEP as variants of uncertain significance. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023)
Eurofins Ntd Llc (ga)	RCV000382015	SCV000339571	uncertain significance	not provided	2016-02-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000674123	SCV000799402	uncertain significance	Glycogen storage disease, type II	2018-04-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000674123	SCV002027318	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674123	SCV002183221	likely pathogenic	Glycogen storage disease, type II	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778032599, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of GAA-related conditions (PMID: 26873529, 30564623; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286228). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000382015	SCV003834081	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000674123	SCV004197916	likely pathogenic	Glycogen storage disease, type II	2022-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586662	SCV005077222	uncertain significance	not specified	2024-04-18	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2799+4A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249970 control chromosomes. c.2799+4A>G has been reported in the literature in an individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease) confirmed by reduced GAA activity in leukocytes and a second individual with Limb-Girdle Muscular Dystrophy (examples: Stepien_2016, Nallamilli_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564623, 26873529). ClinVar contains an entry for this variant (Variation ID: 286228). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000674123	SCV005653260	likely pathogenic	Glycogen storage disease, type II	2024-04-19	criteria provided, single submitter	clinical testing