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rs199951626

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_000152.5(GAA):c.-32-13T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,567,516 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0054 ( 23 hom. )

Consequence

GAA
NM_000152.5 splice_polypyrimidine_tract, intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:48O:1

Conservation

PhyloP100: -0.419
Variant links:
Genes affected
GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5
Variant 17-80104542-T-G is Pathogenic according to our data. Variant chr17-80104542-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80104542-T-G is described in Lovd as [Pathogenic]. Variant chr17-80104542-T-G is described in Lovd as [Likely_pathogenic]. Variant chr17-80104542-T-G is described in Lovd as [Pathogenic]. Variant chr17-80104542-T-G is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAANM_000152.5 linkuse as main transcriptc.-32-13T>G splice_polypyrimidine_tract_variant, intron_variant ENST00000302262.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAAENST00000302262.8 linkuse as main transcriptc.-32-13T>G splice_polypyrimidine_tract_variant, intron_variant 1 NM_000152.5 P1

Frequencies

GnomAD3 genomes
AF:
0.00376
AC:
572
AN:
152120
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00740
Gnomad ASJ
AF:
0.00663
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00550
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00344
AC:
759
AN:
220344
Hom.:
1
AF XY:
0.00373
AC XY:
450
AN XY:
120534
show subpopulations
Gnomad AFR exome
AF:
0.000880
Gnomad AMR exome
AF:
0.00274
Gnomad ASJ exome
AF:
0.00523
Gnomad EAS exome
AF:
0.000225
Gnomad SAS exome
AF:
0.00190
Gnomad FIN exome
AF:
0.000189
Gnomad NFE exome
AF:
0.00530
Gnomad OTH exome
AF:
0.00527
GnomAD4 exome
AF:
0.00542
AC:
7665
AN:
1415278
Hom.:
23
Cov.:
29
AF XY:
0.00545
AC XY:
3810
AN XY:
699350
show subpopulations
Gnomad4 AFR exome
AF:
0.000674
Gnomad4 AMR exome
AF:
0.00267
Gnomad4 ASJ exome
AF:
0.00510
Gnomad4 EAS exome
AF:
0.000128
Gnomad4 SAS exome
AF:
0.00216
Gnomad4 FIN exome
AF:
0.000281
Gnomad4 NFE exome
AF:
0.00641
Gnomad4 OTH exome
AF:
0.00422
GnomAD4 genome
AF:
0.00376
AC:
572
AN:
152238
Hom.:
1
Cov.:
32
AF XY:
0.00333
AC XY:
248
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00118
Gnomad4 AMR
AF:
0.00739
Gnomad4 ASJ
AF:
0.00663
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00550
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00484
Hom.:
0
Bravo
AF:
0.00359
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:48Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:29Other:1
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityJan 29, 2019- -
Pathogenic, criteria provided, single submitterclinical testingDASASep 02, 2021The c.-32-13T>G variant is the most common, seen in 36% to 90% of individuals affected with Glycogen storage disease, type II (OMIM: 606800.0006; PMID: 7881425; 7717400; 7668832; 8558570; 11071489; 14695532; 16433701; 16531044; 16917947; 17210890; 17723315; 17643989; 17616415; 18607768; 19588081; 20350966; 21550241; 20559845; 20301438; GeneOne, DASA), and ClinVar contains an entry for this variant (Variation ID: 4027) - PS4; well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product indicates that the variant causes aberrant splicing of the GAA RNA, resulting in most transcripts lacking exon 2 containing the canonical start codon (PMID: 7881425) - PS3; variant detected in trans with a pathogenic variant (PMID: 27649523) - PM3_strong; this variant is present in population databases (rs386834236 - gnomAD 0.376% frequency; ABraOM 0.29% - http://abraom.ib.usp.br/) - BS1; In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsOct 27, 2021A heterozygous variant in intron 1 of the GAA gene that affects the position 13 nucleotides upstream to exon 2 was detected. The observed variant c.-32-13T>G has a minor allele frequency of 0.3% and 0.4% in the 1000 genomes and gnomAD database respectively. The variant has been previously reported in patients affected with adult-onset glycogen storage disease type-II (Dardis et al. 2014). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic variant. -
Pathogenic, criteria provided, single submitterclinical testingServicio Canario de Salud, Hospital Universitario Nuestra Sra. de CandelariaApr 22, 2022The c.-32-13T>G in compound heterocigosity with c.118C>T (p.Arg40Ter) GAA variant has been reported in our laboratory in a 52-year-old woman from England with diagnosis of Pompe disease (onset 10 years before) with parents and four asymptomatic children and alpha-1,4-glucosidase lysosomal enzyme activity study: 0.4 µmol/L/h (cut-off value: >2.0). Pompe Variant Database describes this phenotype in eight patients, all diagnosed between the ages of 20 and 60. It has been previously reported in patients with Pompe disease adult-onset GSDII (PMID: 7881425, 24150945, 16917947; 17210890; 27189384). This variant is present in population databases ( gnomAD allele frequency 0.003401). ClinVar contains an entry for this variant (Variation ID: 4027). Functional studies demonstrate that this variant results in aberrant gene splicing (PMID: 24150945). In summary, c.-32-13T>G GAA variant meets our criteria to be classified as pathogenic for late-onset glycogen storage disease type II in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals. -
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 24590251, 22613277, 26231297, 24245577, PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 7717400, PS3_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004027). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 08, 2021This variant was identified in trans as compound heterozygous with NM_000152.5:c.307T>G. -
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-The GAA c.-32-13T>G variant was previously observed in Pompe disease (PMID: 16917947; 17210890; 27189384). -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 18, 2019NM_000152.3(GAA):c.-32-13T>G(aka IVS1-13T>G) is classified as pathogenic in the context of Pompe disease. The variant is seen in 36% to 90% of late-onset Pompe disease and is typically associated with late onset. Sources cited for classification include the following: PMID 24150945, 24158270, 16702877, 21439876, 7881425, 22595200 and 24590251. Classification of NM_000152.3(GAA):c.-32-13T>G(aka IVS1-13T>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The GAA c.-32-13T>G variant has been reported in at least six studies and is found in a total of 248 individuals with glycogen storage disease type II, including 151 in a compound heterozygous state and 38 in a heterozygous state in whom a second variant in the GAA gene was not found. Zygosity was not specified for 59 of the 248 patients (Huie et al. 1994; Hermans et al. 2004; Montalvo et al. 2006; Kroos et al. 2007; van Capelle et al. 2016; Lukacs et al. 2016). Patients with the c.-32-13T>G variant were found overall to be more severely affected (van Capelle et al. 2016). The variant was absent from 29 controls and is reported at a frequency of 0.00572 in the European American population of the Exome Sequencing Project. Functional studies have shown the presence of the c.-32-13T>G variant causes aberrant splicing, resulting in exclusion of exon 2 in the processed transcript (Huie et al. 1994). Based on the evidence, the c.-32-13T>G variant is classified as pathogenic for glycogen storage disease type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 03, 2022The c.-32-13T>G variant in GAA is a well-established pathogenic variant for glycogen storage disease type II (GSD2). This is the most common variant in Caucasian individuals with late-onset GSD2, though it is rarely identified in individuals with the infantile-onset form of the disorder (Kroos 2007 PMID: 17210890, Byrne 2011 PMID: 21439876). This variant segregated with disease in many affected relatives from multiple families (Wens 2013 PMID: 24245577). The c.-32-13T>G variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 4027) and has been identified in 0.55% (45/8122) of Ashkenazi Jewish and in 0.5% (614/116004) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is located in the 3' splice region. Functional studies have demonstrated that this variant alters splicing of the GAA transcript, leading to reduced expression of functional GAA enzyme (Dardis 2014 PMID: 24150945). In summary, despite its high frequency in the general population, the c.-32-13T>G variant meets criteria to be classified as pathogenic for late-onset glycogen storage disease type II in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3_Supporting. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 03, 2017Variant summary: The GAA variant, c.-32-13T>G, alters a non-conservative nucleotide and 3/5 in silico splicing tools predict this variant to have a moderate effect on splicing pattern consistent with loss of function as the established mechanism of action of disease. These predictions were confirmed by Boerkoel_1995, who showed that this variant leads to exon 2 skipping with a low level of normal mRNA also being transcribed (aka leaky splicing). The leakage of the normal transcript is likely responsible for the remaining low level of GAA activity and late-onset clinical presentation. This variant is attributed to ~70% of late onset Pompe cases, has been reported in trans with several pathogenic variants and segregates with disease in multiple affected individuals in several families. The variant of interest has been reported as Pathogenic by several reputable databases/clinical laboratories dating back from 2007 to present. Taking together, the variant has been classified as "pathogenic." -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 24, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease II (MIM#232300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Experimental studies using patient fibroblasts demonstrated abberant splicing which yields two splicing outcomes, one in which intron 1 is fully spliced out and the other in which 36 nucleotide of intron 1 is retained (PMID: 24150945). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (854 heterozygotes, 1 homozygote). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants associated with adult-onset Pompe disease (ClinVar) however it has also been reported in patients with early and infantile onset Pompe disease. It has been reported in mostly compound heterozygous but also rarely in homozygous individuals, where incomplete penetrance or environmental factors suggested to affect disease onset (ClinVar, PMID: 26231297, PMID: 17210890). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyDec 29, 2022The GAA c.-32-13T>G variant is classified as Likely Pathogenic (PS3_Moderate, PM3_Very_Strong, PP4_moderate) GAA c.-32-13T>G is located in intron 1/19. Functional studies show that the variant results in an increased amount of aberrant splicing and a reduction in normal spliced mRNA. Some residual normal spliced mRNA remains, possibly accounting for the late onset of disease. This variant has been reported as a Class A severity variant (PMID:24510945, 7717400, 18425781) (PS3_moderate). This variant has been detected in trans with a pathogenic variant in affected patients and is considered the most common GAA variant in patients with adult onset Pompe disease (PMID:16917947, 17210890, 27189384, 7881425, 7717400) (PM3_Very strong). The variant has been reported in dbSNP (rs386834236), as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4027) and as disease causing in HGMD (CS941489). The clinical features of this case are highly specific for a variant in the GAA gene (PMID:18425781) (PP4_moderate). -
Pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoSep 01, 2021This sequence change is an intronic substitution in intron 1, c.-32-13T>G (also known as c.-45T>G). This sequence change has been reported in several individuals with adult-onset glycogen storage disease type II /Pompe disease in both homozygous and compound heterozygous states (PMID: 7881425, 24590251, 21439876, 22613277, 26231297, 24245577). Functional in vivo studies have shown that this sequence change abrogates the binding of the splicing factor U2AF65 to the polypyrimidine tract of exon 2 resulting in aberrant gene splicing (PMID: 24150945). This sequence change has also been termed as a 'leaky splice' variant, as it produces some percentage of the normal amount of messenger RNA which results in a proportional amount of structurally and functionally normal acid a-glucosidase (PMID: 22253258,17210890). This sequence change has been described in the gnomAD database with an overall population frequency of 0.3%. Based on these evidence, the c.-32-13T>G variant is classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingLaboratorio de Medicina Genomica, Hospital General de Culiacan-The observed phenotype is merely musculoskeletal. Dyspnea on exertion, difficulty in both genuflection and climbing stairs, progressive muscle weakness in pelvic area, amyotrophy, hyperflexia, early fatigue, myalgias and cramps, Gowers sign were observed in all siblings, while weakness in arms, scapula alata and progresive muscle weakness in scapula area were observed in males only. -
Pathogenic, criteria provided, single submittercurationLaboratory of Medical Genetics, National & Kapodistrian University of AthensFeb 01, 2024- -
Pathogenic, criteria provided, single submitterclinical testingBreda Genetics srlApr 30, 2021The variant c.-32-13T>G in the GAA gene is reported as pathogenic for glycogen storage disease type 2 (Pompe disease) in ClinVar (Variation ID: 4027) and as pathogenic in the Global Variome shared LOVD database v.3.0. The variant was firstly identified by Huie et al., 1994 (PMID: 7881425) in a patient with late onset Pompe disease. Subsequent functional studies have clarified that this variant alters the splicing process, leading to the production of a transcript with exon 2 deletion, although a low amount of normal transcript is produced, which may explain the role of this variant in late forms of the disease (Boerkoel et al., 1995, PMID: 7717400; Dardis et al., 2014, PMID: 24150945). This variant represents a common mutation that is present in approximately 40% -70% of alleles in patients with late forms (PMID: 24150945). According to Leslie et Bailey, 2017 (PMID: 20301438) the variant is observed in 36% to 90% of late-onset Pompe disease cases. The variant is reported with an estimated allelic frequency of 0.003445 in gnomAD exomes and 0.003094 in gnomAD genomes, with one homozygous individual reported. -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 30, 2016c.-32-13T>G, an intronic variant, accounts for 36% - 90% of late-onset Pompe disease (GeneReviews: Leslie and Tinkle, update 2013). It has been reported in trans with a pathogenic variant and segregates with disease in multiple affected individuals in several families (Kroos et al. 2007). Functional studies have shown that this variant affect splicing and causes reduction in the enzyme activity (Boerkoel CF et al., 1995; Kroos et al. 200). A reputable clinical diagnostic laboratory (Emory Genetics Laboratory) has also classified this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.-32-13T>G as a recessive Pathogenic variant for Glycogen storage storage disease type II. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change falls in intron 1 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 is likely to result in the loss of the initiator methionine. This variant is present in population databases (rs386834236, gnomAD 0.6%), including at least one homozygous and/or hemizygous individual. This variant is a well documented cause of late-onset Pompe disease among individuals of European ancestry, and it has also been reported in affected individuals of other ethnicities (PMID: 7881425, 24590251, 21439876, 22613277, 26231297, 24245577). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4027). Experimental studies have shown that this variant interferes with mRNA splicing of exon 1 of the GAA gene. The effect is such that it allows for some normally spliced transcript to be produced, which is thought to contribute to its role in late-onset as opposed to early-onset Pompe disease (PMID: 7881425, 2510307). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 30, 2024- -
Likely pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 17, 2024- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 28, 2023The GAA c.-32-13T>G variant (rs386834236), also known as c.-45T>G, is reported in the literature in multiple individuals affected with adult-onset Pompe disease (Beltran Papsdorf 2014, Boerkoel 1995, Dardis 2014, Golsari 2018, Gort 2007, Kroos 1995, Montalvo 2006, Musumeci 2015, Sacconi 2014). This variant is reported in ClinVar (Variation ID: 4027), and is found in the general population with an overall allele frequency of 0.34% (856/251,700 alleles, including a single homozygote) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Functional characterization indicates that the variant causes aberrant splicing of the GAA RNA, resulting in most transcripts lacking exon 2 containing the canonical start codon (Boerkoel 1995, Dardis 2014). However, small amounts of full-length transcripts is still generated, resulting in varying amount of residual GAA activity in the patients (Gort 2007, Kroos 1995, Musumeci 2015, Sacconi 2014). Based on available information, the c.-32-13T>G variant is considered to be pathogenic. References: Beltran Papsdorf T et al. Pearls & Oy-sters: clues to the diagnosis of adult-onset acid maltase deficiency. Neurology. 2014 82(9):e73-5. PubMed: 24590251. Boerkoel C et al. Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II. Am J Hum Genet. 1995 Apr;56(4):887-97. PMID: 7717400. Dardis A et al. Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents. Nucleic Acids Res. 2014 42(2):1291-302. PubMed: 24150945. Golsari A et al. Prevalence of adult Pompe disease in patients with proximal myopathic syndrome and undiagnosed muscle biopsy. Neuromuscul Disord. 2018 Mar;28(3):257-261. PubMed: 29326002. Gort L et al. Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G>C mutation. Mol Genet Metab. 2007 92(1-2):183-7. PMID: 17616415. Kross M et al. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. J Med Genet. 1995 32(10):836-7. PMID: 17210890. Montalvo A et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat. 2006 27(10):999-1006. PMID: 16917947. Musumeci O et al. Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum. Neuromuscul Disord. 2015 25(9):719-24. PMID: 26231297. Sacconi S et al. Atrio-ventricular block requiring pacemaker in patients with late onset Pompe disease. Neuromuscul Disord. 2014 24(7):648-50. PMID: 24844452. -
Pathogenic, criteria provided, single submitterclinical testing;provider interpretationKids Neuroscience Centre, Sydney Children's Hospitals Network-Splicing abnormalities, predominantly exon-2 skipping, due to the c.-32-13T>G pathogenic variant were confirmed by RT-PCR. -
Pathogenic, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NG_009822.1(NM_000152.3):c.-32-13T>G in the GAA gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that this variant interferes with mRNA splicing of exon 1 of the GAA gene. Wen ey al reported 22 families with Pompe disease. All carried the most common mutation c.-32-13 T to G in combination with another pathogenic mutation (PMID: 24245577).The patient's phenotype is highly specific for GAA gene (PMID: 7881425; 2510307). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4. -
Pathogenic, criteria provided, single submitterresearchBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJun 25, 2017The c.-32-13 T>G pathogenic variant in the GAA gene is a common variant that has been reported in 36-90% of patients with adult-onset GSDII (PMID: 7881425; PMID: 24150945). Functional studies demonstrate that the c.-32-13 T>G mutation results in aberrant gene splicing (PMID: 24150945). -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Pathogenic:13
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 06, 2015- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenFeb 01, 2021- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 18, 2021Common pathogenic variant reported in 36-90% of individuals with adult-onset GSDII (Huie et al., 1994; Dardis et al., 2014); Functional studies demonstrate that the c.-32-13 T>G variant results in aberrant gene splicing (Dardis et al., 2014); This variant is associated with the following publications: (PMID: 29556838, 32528171, 32721234, 8990003, 28629821, 30275481, 31086307, 31980526, 32071926, 31676142, 23417379, 30314719, 30564623, 30827497, 21967859, 28694071, 15986226, 28951071, 29181627, 16531044, 29326002, 7881425, 26231297, 25673129, 26350092, 21228398, 21109266, 27708273, 28032299, 27460347, 27170567, 22975760, 26800218, 25846667, 24150945, 16917947, 24844452, 25103075, 22595200, 21439876, 22613277, 24158270, 24590251) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024GAA: PM3:Very Strong, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 23, 2022- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 26, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 03, 2023- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 06, 2016- -
Glycogen storage disease II, adult form Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2007- -
Glycogen storage disease due to acid maltase deficiency, late-onset Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This sequence change falls in intron 1 of GAA. The variant is present in a large population cohort at a frequency of 0.3% (rs386834236, 856/251,700 alleles, 1 homozygote in gnomAD v2.1). It is the most commonly reported variant (homozygous or with a second pathogenic allele) in individuals affected by the late-onset form of glycogen storage disorder type II confirmed by reduced enzyme activities in lymphocytes/muscle tissue, and segregates with disease (PMID: 7881425, 16917947, 26231297). Multiple lines of computational evidence predict no significant splice defect (SpliceAI, MaxEntScan, NNSplice). However, functional assays demonstrate the variant has a leaky splice effect by abrogating binding of splice factors to the exon 2 polypyrimidine tract leading to a significant increase in aberrantly spliced transcripts with some expression of the full-length transcript from the variant allele (PMID: 24150945). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PP1, PP4. -
Glycogen storage disease, type IV Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 19, 2022- -
GAA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 16, 2023The GAA c.-32-13T>G variant is located in the 5' untranslated region. This variant has been clearly documented as causative for glycogen storage disease type II when present in trans with another pathogenic GAA variant. The c.-32-13T>G variant is the most common pathogenic variant found in adults with glycogen storage disease type II/late-onset Pompe disease (GSD II/ LOPD) (Huie et al. 1994. PubMed ID: 7881425; Hermans et al. 2004. PubMed ID: 14695532). This variant leads to aberrant splicing of exon 2, which contains the start codon (Dardis et al. 2014. PubMed ID: 24150945). Please note that in the literature, this variant may also be referred to as c.-45T>G or IVS1-13T>G. In summary, this variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2023The c.-32-13T>G alteration is located in the 5' untranslated region (5'UTR) of the GAA gene. This alteration consists of a T to G substitution 13 nucleotides upstream of exon 2 (coding exon 1). Based on data from gnomAD, the G allele has an overall frequency of 0.34% (856/251700) total alleles studied. The highest observed frequency was 0.554% (45/8122) of Ashkenazi Jewish alleles. The c.-32-13T>G alteration is the most frequent mutation seen in late-onset GSD II patients (36-90%) and is not associated with infantile-onset Pompe disease (Montalvo, 2006; Hermans, 2004). This nucleotide position is not well conserved in available vertebrate species. The c.-32-13T>G alteration leads to a leaky splice site, giving rise to alternatively spliced transcripts with deletion of the first coding exon (exon 2), but still produces a low amount of normally processed mRNA. This results in greatly diminished, but not absent, GAA enzyme activity of 10-20% (Dardis, 2014). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic. -
Myopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
2.9
DANN
Benign
0.62
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386834236; hg19: chr17-78078341; API