ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2238G>C (p.Trp746Cys) (rs1800312)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254988 SCV000321685 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Nio MY, 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24444888, 9535769, 21232767, 21757382, 18458862, 23430493, 25526786, 28433475, 27363342, 29451150, 30943998, 31953985, 31980526, 30275481, 31589614)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000254988 SCV000333710 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000283919 SCV000407295 pathogenic Glycogen storage disease, type II 2017-04-27 criteria provided, single submitter clinical testing The GAA c.2238G>C (p.Trp746Cys) variant has been reported in at least six studies in which it is found in a total of 31 individuals with glycogen storage disease, type II, including three in a homozygous state, 27 in a compound heterozygous state, and one in a heterozygous state in whom a second variant was not identified (Huie et al. 1994; Wan et al. 2008; Yang et al. 2011; Liu et al. 2014; Liong et al. 2014; Zhang et al. 2016). Ten of the compound heterozygous individuals were found to carry a second GAA variant in cis with the p.Trp746Cys variant (Huie et al. 1994; Yang et al. 2011). However, functional studies in cell lines demonstrated that expression of the p.Trp746Cys variant alone resulted in enzymatic activity that was 10-29% of wild type GAA activity (Huie et al. 1994; Huie et al. 1998; Yang et al. 2011; Nino et al. 2013). The p.Trp746Cys variant was absent from 100 controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Trp746Cys 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000283919 SCV000603775 pathogenic Glycogen storage disease, type II 2019-09-04 criteria provided, single submitter clinical testing The GAA c.2238G>C; p.Trp746Cys variant (rs1800312; ClinVar Variation ID: 265160) has been identified in several individuals, both as a homozygote and in trans other pathogenic GAA variants, included in cohorts of late stage/juvenile onset Pompe disease (Yang 2011, Liu 2014, Wan 2008, Lee 2017, Liu 2018, Zhao 2019), and is the most commonly identified variant in Chinese and Taiwanese Pompe patients. Functional assessment of the p.Trp746Cys variant has revealed this variant significantly reduces GAA enzyme active compared to wild-type, although some residual activity remains (Yang 2011 and Nino 2013). Additionally, four other amino acid substitutions at codon 746 have been associated with Pompe disease: p.Trp746Arg (Nino 2013), p.Trp746Leu (Wittmann 2012), p.Trp746Gly (Labrousse 2010), and p.Trp746Ser (Kroos 2008). Functional characterization of these changes demonstrated that all have a varied impact on GAA enzyme function; ranging from less severe (p.Trp746Arg and p.Trp746Gly), to probably non-pathogenic (p.Trp746Ser) (Nino 2013). Thus, the p.Trp746Cys variant satisfies our criteria for classification as pathogenic. References: Kroos et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008; 29(6): E13-26. Labrousse et al. Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. Mol Genet Metab. 2010; 99(4): 379-383. Lee JH et al. Targeted population screening of late onset Pompe disease in unspecified myopathy patients for Korean population. Neuromuscul Disord. 2017 Jun;27(6):550-556 Liu et al. Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation. BMC Med Genet. 2014; 15:141. Liu HX et al. Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease. Chin Med J (Engl). 2018 Feb 20;131(4):448-453. Nino et al. Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease. JIMD Rep. 2013; 7: 39-48. Wan et al. Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II. J Neurol. 2008; 255(6): 831-838. Wittmann et al. Newborn screening for lysosomal storage disorders in hungary. JIMD Rep. 2012; 6: 117-125. Yang et al. Rapid progressive course of later-onset Pompe disease in Chinese patients. Mol Genet Metab. 2011; 104(3): 284-288. Zhao et al. Characteristics of Pompe disease in China: a report from the Pompe registry. Orphanet J Rare Dis. 2019 Apr 3;14(1):78.
Invitae RCV000283919 SCV000626554 pathogenic Glycogen storage disease, type II 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 746 of the GAA protein (p.Trp746Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs1800312, ExAC 0.05%). This variant has been reported in the literature in multiple individuals affected with Pompe disease both in the heterozygous and in the homozygous state (PMID: 18458862, 21757382, 21232767, 23430493, 25526786, 27099502) and it is considered a mild/moderate late-onset Pompe disease variant (PMID: 21232767, 25526786, 27099502, 25093132). ClinVar contains an entry for this variant (Variation ID: 265160). Experimental studies have shown that this missense change causes a moderate reduction on GAA enzyme activity in vitro (PMID: 21757382, 9535769, 7981676). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000283919 SCV000695651 pathogenic Glycogen storage disease, type II 2016-03-03 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000283919 SCV000803623 likely pathogenic Glycogen storage disease, type II 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Glycogen storage disease 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:18458862).
Fulgent Genetics,Fulgent Genetics RCV000283919 SCV000893477 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825562 SCV000966888 pathogenic Glycogen storage disease 2018-08-08 criteria provided, single submitter clinical testing The p.Trp746Cys variant in GAA has been reported in at least 2 homozygous and 24 compound heterozygous Asian individuals with juvenile- or adult-onset glycogen storage disease type II (GSDII) also known as Pompe disease (Wan 2008, Chien 20 11, Yang 2011, Liu 2014, Liong 2014, Zhang 2016, Lee 2017, Park 2017), and segre gated with GSDII in 3 affected relatives from 2 families (Yang 2011, Liu 2014). This variant has been identified in 72/126398 European and 6/18864 East Asian ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs1800312). Although this variant has been seen in the general pop ulation, its frequency is low enough to be consistent with a recessive carrier f requency. Computational prediction tools and conservation analysis suggest that the p.Trp746Cys variant may impact the protein. In vitro functional studies prov ide some evidence that the p.Trp746Cys variant may impact protein function (Huie 1994, Huie 1998, Yang 2011, Nino 2013). In summary, this variant meets criteria to be classified as pathogenic for GSDII in an autosomal recessive manner. ACMG /AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP1, PP3, PP4.
Myriad Women's Health, Inc. RCV000283919 SCV001194239 pathogenic Glycogen storage disease, type II 2019-12-24 criteria provided, single submitter clinical testing NM_000152.3(GAA):c.2238G>C(W746C) is classified as pathogenic in the context of Pompe disease. Sources cited for classification include the following: PMID 25093132, 9535769, 23430493, 25526786, 21757382 and 27099502. Classification of NM_000152.3(GAA):c.2238G>C(W746C) 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.‚Äã
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254988 SCV001245694 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000283919 SCV001425406 pathogenic Glycogen storage disease, type II 2020-05-21 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000254988 SCV000800888 pathogenic not provided 2017-01-03 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000283919 SCV001422883 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp746Cys variant in GAA has been reported in at least 35 individuals (including 26 in China, 5 in Taiwan, and 1 in Malaysia) with Glycogen Storage Disease II (PMID: 21757382, 25526786, 18458862, 7981676, 21232767, 25093132, 27099502, 29120458, 29095275, 28433475, 27099502), and has also been reported pathogenic by 10 submitters and likely pathogenic by 1 submitter in ClinVar (Variation ID: 265160). This variant has been identified in 0.057% (73/128684) of European (non-Finnish) chromosomes and 0.035% (7/19948) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800312). 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 with transfected cells provide some evidence that the p.Trp746Cys variant may impact GAA activity protein levels (PMID: 21757382, 23430493, 9535769). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with reported pathogenic and likely pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Cys variant is pathogenic (PMID: 25093132, 25526786, 18458862). Four additional variants at the same position (p.Trp746Gly, p.Trp746Arg, p.Trp746Leu, and p.Trp746Ser), are pathogenic, likely pathogenic, or reported in association with disease in ClinVar (Variation ID: 556431, 499293, 284776, 188484). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 25526786, 18458862, 21757382, 21232767). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with pathogenic and likely pathogenic variants in individuals with Glycogen Storage Disease II and in vitro functional studies with transfected cells. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2, PP3, PP4 (Richards 2015).
Natera, Inc. RCV000283919 SCV001463857 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000254988 SCV001931394 likely pathogenic not provided no assertion criteria provided clinical testing

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