ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.-32-13T>G (rs386834236)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000055770 SCV000223928 pathogenic Glycogen storage disease, type II 2016-03-30 criteria provided, single submitter clinical testing c.-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.
Ambry Genetics RCV000210721 SCV000263014 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000153285 SCV000280615 pathogenic not provided 2015-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000153285 SCV000321682 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The c.-32-13 T>G variant in the GAA gene is a common pathogenic variant that has been reported in 36-90% of individuals with adult-onset glycogen storage disease type II (Huie et al., 1994; Dardis et al., 2014). The c.-32-13 T>G variant is observed in 614/116,004 (0.53%) alleles from individuals of non-Finnish European background and 856/251,700 (0.34%) total alleles in large population cohorts, including 1 homozygous individual (Lek et al., 2016). Functional studies demonstrate that the c.-32-13 T>G variant results in aberrant gene splicing (Dardis et al., 2014). In summary, we interpret c.-32-13 T>G as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000055770 SCV000407251 pathogenic Glycogen storage disease, type II 2017-04-27 criteria provided, single submitter clinical testing The 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.
Genetic Services Laboratory, University of Chicago RCV000055770 SCV000594900 pathogenic Glycogen storage disease, type II 2016-05-23 criteria provided, single submitter clinical testing
Invitae RCV000055770 SCV000626604 pathogenic Glycogen storage disease, type II 2020-01-07 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the GAA mRNA. It does not directly change the encoded amino acid sequence of the GAA protein. This variant is present in population databases (rs386834236, ExAC 0.5%). 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). 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.
Broad Institute Rare Disease Group,Broad Institute RCV000055770 SCV000693906 pathogenic Glycogen storage disease, type II 2017-06-25 criteria provided, single submitter research The 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).
Integrated Genetics/Laboratory Corporation of America RCV000055770 SCV000695660 pathogenic Glycogen storage disease, type II 2017-05-03 criteria provided, single submitter clinical testing Variant 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."
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153285 SCV000700287 pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000611160 SCV000712481 pathogenic Glycogen storage disease 2020-04-14 criteria provided, single submitter clinical testing The 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626740 SCV000747443 pathogenic Myopathy 2017-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000055770 SCV000782601 pathogenic Glycogen storage disease, type II 2017-03-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000055770 SCV000894159 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000055770 SCV001140840 pathogenic Glycogen storage disease, type II 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000055770 SCV001157575 pathogenic Glycogen storage disease, type II 2018-11-29 criteria provided, single submitter clinical testing The 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 as pathogenic by multiple laboratories 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. 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. 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. 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. 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. 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. 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. 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. Sacconi S et al. Atrio-ventricular block requiring pacemaker in patients with late onset Pompe disease. Neuromuscul Disord. 2014 24(7):648-50.
Myriad Women's Health, Inc. RCV000055770 SCV001194223 pathogenic Glycogen storage disease, type II 2019-12-18 criteria provided, single submitter clinical testing NM_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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000153285 SCV001245683 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000055770 SCV001251463 pathogenic Glycogen storage disease, type II criteria provided, single submitter research The GAA c.-32-13T>G variant was previously observed in Pompe disease (PMID: 16917947; 17210890; 27189384).
OMIM RCV000004242 SCV000024408 pathogenic Glycogen storage disease II, adult form 2007-09-01 no assertion criteria provided literature only
GeneReviews RCV000055770 SCV000086729 pathologic Glycogen storage disease, type II 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Laboratorio de Medicina Genomica, Hospital General de Culiacan RCV000055770 SCV000680487 pathogenic Glycogen storage disease, type II no assertion criteria provided clinical testing 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000153285 SCV000800856 pathogenic not provided 2016-09-15 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000055770 SCV001132809 pathogenic Glycogen storage disease, type II 2019-01-29 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000055770 SCV001142478 pathogenic Glycogen storage disease, type II 2020-01-06 no assertion criteria provided curation NG_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.

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