ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.546G>A (p.Thr182=) (rs143523371)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723387 SCV000330940 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000385549 SCV000538029 pathogenic Glycogen storage disease, type II 2016-03-30 criteria provided, single submitter clinical testing The c.546G>A (p.Thr182=) synonymous/splice variant in the GAA gene has been previously reported in in trans with another pathogenic variant (c.525delT) in one individual affected with a mild, late-onset form of GSDII (Hermans et al., 2004). This variant is located near the canonical splice donor-site in intron 2 (last coding nucleotide in exon 2) of the GAA gene. mRNA expression studies from the affected individual’s fibroblasts showed that this variant reduced gene expression (6.3% relative to control) along with reduced alpha-glucosidase activity (3% relative to control); however, abnormally spliced transcripts were not observed (Hermans et al., 2004). Other single nucleotide variants at the same coding position (c.546) have been reported in affected individuals displaying a milder phenotype (Gort et al., 2007; Maimaiti et al., 2009; Kobayashi et al., 2010; Shimada et al., 2011). Furthermore, Tsuburaya RS et al., (2012), identified a c.546G>T variant in the homozygous state in two individuals with adult-onset Pompe disease and showed, by RNA splicing studies, that this variant resulted in exon 2 skipping and reduced enzymatic activity (7.5% and 12.3% respectively). The c.546G>A variant is reported at low frequency in the population databases (Exome Sequencing Project [ESP] = 0.024%; 1000 Genomes = 0.4%; ExAC = 0.036%). In silico splicing algorithms predict this variant will result in abnormal splicing (Human Splice Finder = Broken WT Donor Site, New ESS Site, ESE Site Broken). Therefore, this collective evidence supports the classification of the c.546G>A (p.Thr182=) as a Pathogenic variant for GSDII; however, variants at this nucleotide position have only been observed in individuals affected with a mild, late-onset form of GSDII.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000385549 SCV000695662 pathogenic Glycogen storage disease, type II 2017-05-03 criteria provided, single submitter clinical testing Variant summary: The c.546G>A (p.Thr182=) in GAA gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant alters a canonical splice sequence. Although no aberrant transcript was experimentally confirmed, authors suspect a leaky splicing, and reduced gene expression resulted in reduced alpha-glucosidase activity (2-5% relative to controls) (Hermans, 2004; Bali, 2011). The variant is present in the control population dataset of ExAC at frequency of 0.000045 (5/111096 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0042, suggesting that it is not a common polymorphism. The variant of interest has been reported in affected individuals with clinically and enzymatically confirmed dx of late onset Pompe disease (GSDII) (Hermans, 2004; Bali, 2011) in trans with another pathogenic variant (c.525delT and c.2041-1G>A respectively). In addition, c.546G appears to be a mutational hot-spot, as other alterations of this nucleotide, c.546G>T and c.546G>C, leading to the same synonymous change (p.Thr182=) were identified in multiple affected GSDII patients and are classified as causative splice-site variants. Lastly, the variant of interest, c.546G>A is cited as Pathogenic by reputable databases/clinical laboratories. Taking together all evidence into consideration and by applying ACMG guidelines, the variant was classified as Pathogenic.
Invitae RCV000385549 SCV000752061 pathogenic Glycogen storage disease, type II 2020-10-14 criteria provided, single submitter clinical testing This sequence change affects codon 182 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. This variant also falls at the last nucleotide of exon 2 of the GAA coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs143523371, ExAC 0.04%). This variant has been reported in several individuals affected with late-onset Pompe disease (PMID: 14695532, 21484825, 25037089). ClinVar contains an entry for this variant (Variation ID: 280955). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change leads to reduced levels of GAA mRNA (PMID: 14695532). A different variant affecting this nucleotide (c.546G>T) has been determined to be pathogenic (PMID: 20202878, 17616415, 19609281, 22196155, 21982629, 21179066). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000385549 SCV000800377 likely pathogenic Glycogen storage disease, type II 2018-06-01 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000385549 SCV001422886 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous c.546G>A (p.Thr182=) variant in GAA has been reported in 4 individuals (including 1 British individual) with Glycogen Storage Disease II (PMID: 21984055, 21484825, 14695532, 25037089), and has also been reported pathogenic (by Invitae, EGL Genetic Diagnostics, Oregon Health and Sciences University, and Integrated Genetics) and likely pathogenic (by Counsyl) in ClinVar (Variation ID: 280955). This variant has been identified in 0.010% (2/19660) of East Asian chromosomes, 0.008503% (2/23522) of African chromosomes, and 0.003% (4/121752) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143523371). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing. The Threonine (Thr) at position 182 is not well conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, this information is not predictive enough to rule out pathogenicity. In vitro functional studies (e.g. RT-PCR) provide some evidence that the c.546G>A variant may significantly reduce GAA expression but may not cause abnormal splicing (PMID: 14695532). However, these types of assays may not accurately represent biological function. The presence of this variant in combination with 2 pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the c.546G>C variant is pathogenic (PMID: 21484825, 25037089). The phenotype of at least two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissue (PMID: 21484825, 25037089). Two additional variants at the same position, c.546G>T and c.546G>C, have been reported as a VUS or likely pathogenic in association with Glycogen Storage Disease II in ClinVar (Variation ID: 370637, 281056). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PP4, PS3_Supporting (Richards 2015).
Natera, Inc. RCV000385549 SCV001453589 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000385549 SCV001550142 pathogenic Glycogen storage disease, type II no assertion criteria provided clinical testing The GAA p.Thr182= variant was identified in 2 of 136 proband chromosomes (frequency: 0.015) from individuals or families with Glycogen-storage disease type II. Sequence variations studies were included one in silico analysis using three Splice Site Prediction (SSP) programs to evaluate the potential effect on splice sites (MaxEntScan, NNSplice and HBond). The c.546G4A mutation does not lead to an amino-acid substitution but modifies the splice donor site of exon 2 “ACAgtgggc instead of ACGgtgggc” (Hermans_2004, Zampieri_2011). The variant was also identified in dbSNP (ID: rs143523371) as “With Likely Pathogenic allele”; in ClinVar and Cllinvitae databases as Pathogenic by Emory Genetics and Knight Diagnostic Laboratories Oregoon Health and Sciences University. In addition, the variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in the NHLBI GO Exome Sequencing Project in 1 of 4134 African American alleles (Freq: 0.0002). The variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, databases. The variant was identified in control databases in 7 of 263174 chromosomes at a frequency of 0.000027 (Genome Aggregation Consortium Feb 27, 2017). The c.546G>A variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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