Submissions for variant NM_000152.5(GAA):c.1552-3C>G

gnomAD frequency: 0.00008  dbSNP: rs375470378

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000593914	SCV002540658	likely pathogenic	Glycogen storage disease, type II	2022-06-03	reviewed by expert panel	curation	The NM_000152.5:c.1552-3C>G variant in GAA is an intronic variant which occurs within intron 10 and is predicted to impact splicing by disrupting the acceptor splice site (PP3). Experimental studies in fibroblasts from a patient that was homozygous for the variant demonstrated that the variant results in the full inclusion of intron 10, which is predicted to introduce a premature termination codon. However, there was some evidence of normal splicing (PMID 6838077, 25243733) (PS3_Moderate). At least 3 patients with Pompe disease have been reported with this variant including 2 patients with documented GAA deficiency (PP4_Moderate) (PMID 16838077, 28196920, 23430949). Of these patients, one is homozygous for the variant (PMID 16838077) and one is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16838077) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002713 (35/129024 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 419722, 2 star review status) with 10 submitters classifying as likely pathogenic or pathogenic and 1 submitter classifying as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/Amp criteria met, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022.
GeneDx	RCV000479616	SCV000567714	pathogenic	not provided	2015-09-01	criteria provided, single submitter	clinical testing	The c.1552-3 C>G variant has been previously reported as a homozygous variant in a patient with a mild form of GSDII (Kroos et al., 2006). Functional studies demonstrate that the c.1552-3 C>G variantcauses aberrant gene splicing and results in reduced enzyme activity (Kroos et al., 2006; Bergsma et al., 2015). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.Therefore, we interpret c.1552-3 C>G as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000479616	SCV000701459	likely pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV000593914	SCV000819326	pathogenic	Glycogen storage disease, type II	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375470378, gnomAD 0.03%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 16838077, 23430949, 25243733, 28196920). ClinVar contains an entry for this variant (Variation ID: 419722). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in multiple aberrant transcripts, the most prominent of which (~80% of total transcript pool) includes all of intron 10 and introduces a premature termination codon (PMID: 16838077, 25243733). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000593914	SCV000917383	pathogenic	Glycogen storage disease, type II	2017-11-06	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.1552-3C>G variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict an impact on normal splicing. Multiple functional studies support these predictions with findings indicating that the variant does affect splicing (Kroos_2006, Bergsma_2015). This variant was found in 38/277142 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000276 (35/126638), which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in homozygous affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000593914	SCV001160509	likely pathogenic	Glycogen storage disease, type II	2019-05-11	criteria provided, single submitter	clinical testing	The GAA c.1552-3C>G variant (rs375470378) is reported in the literature in at least one homozygous individual affected with glycogen storage disease II, also called Pompe disease (Bergsma 2015, Kroos 2006). This variant is found in the non-Finnish European population with an overall allele frequency of 0.03% (35/129024 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical acceptor splice site. Consistent with these predictions, analyses of patient cDNAs show production of aberrantly spliced mRNAs and reduced mRNA levels compared to those in healthy individuals (Bergsma 2015, Kroos 2006). In addition, fibroblasts from a homozygous individual with this variant exhibited decreased GAA protein levels and substantially reduced GAA enzymatic activity (Bergsma 2015, Kroos 2006). Based on available information, this variant is considered to be likely pathogenic. References: Bergsma AJ et al. Identification and characterization of aberrant GAA pre-mRNA splicing in pompe disease using a generic approach. Hum Mutat. 2015 Jan;36(1):57-68. Kroos M et al. Seven cases of Pompe disease from Greece. J Inherit Metab Dis. 2006 Aug;29(4):556-63.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000593914	SCV001370134	pathogenic	Glycogen storage disease, type II	2019-01-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000593914	SCV001422910	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1552-3C>G variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 16838077, 25243733, 28196920) and has also been reported likely pathogenic by Counsyl, Invitae, and EGL Genetic Diagnostics and pathogenic by GeneDx and Integrated Genetics in ClinVar (Variation ID: 419722). This variant has been identified in 0.027% (35/129024) of European (non-Finnish) chromosomes and 0.008% (3/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375470378). 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 provide some evidence that the c.1552-3C>G variant may cause an impact on splicing in individuals homozygous for this variant with less than 9% of mRNA spliced correctly (PMID: 25243733, 16838077). However, these types of assays may not accurately represent biological function. This variant is located in the 3' splice region. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein, though some splice predictors do suggest an impact on a splice site. The presence of this variant in the homozygous state and in combination with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the c.1552-3C>G variant is pathogenic (PMID: 28196920, 16838077). The phenotype of individuals homozygous and heterozygous with this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their leukocytes and the absence of known pseudodeficiency alleles in one individual (PMID: 28196920, 16838077). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP4_Moderate, PM3, PM2, PS3_Supporting (Richards 2015).
Genome-Nilou Lab	RCV000593914	SCV001810210	pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000479616	SCV002025200	likely pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000593914	SCV002060267	likely pathogenic	Glycogen storage disease, type II	2021-11-08	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1552-3C>G is an intronic variant classified as likely pathogenic in the context of Pompe disease. c.1552-3C>G has been observed in cases with relevant disease (PMID: 28196920, 16838077, 23430949, 33202836). Functional assessments of this variant are available in the literature (PMID: 16838077, 25243733, 27623443). c.1552-3C>G has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_000152.3(GAA):c.1552-3C>G is an intronic variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
AiLife Diagnostics, AiLife Diagnostics	RCV000479616	SCV002501926	likely pathogenic	not provided	2021-09-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000593914	SCV002781578	pathogenic	Glycogen storage disease, type II	2022-03-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479616	SCV003917980	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	GAA: PM2, PM3, PP3, PS3:Supporting
Ambry Genetics	RCV003380590	SCV004088426	likely pathogenic	Cardiovascular phenotype	2023-07-17	criteria provided, single submitter	clinical testing	The c.1552-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 10 in the GAA gene. This alteration has been reported as homozygous and compound heterozygous in individuals with Pompe disease, including those with low enzyme activity (Kroos M et al. J Inherit Metab Dis, 2006 Aug;29:556-63; Wittmann J et al. JIMD Rep, 2012 Mar;6:117-25; Lin N et al. Clin Chem, 2017 Apr;63:842-851; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6:[ePub ahead of print]). Additionally, aberrant splicing was observed in an in vitro study (Kroos M et al. J Inherit Metab Dis, 2006 Aug;29:556-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV000593914	SCV004195414	likely pathogenic	Glycogen storage disease, type II	2023-10-31	criteria provided, single submitter	clinical testing