ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2014C>T (p.Arg672Trp) (rs757111744)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725325 SCV000336054 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000169099 SCV000407286 pathogenic Glycogen storage disease, type II 2017-04-28 criteria provided, single submitter clinical testing The GAA c.2014C>T (p.Arg672Trp) variant was identified in a compound heterozygous state in at least 11 individuals with late-onset glycogen storage disease type II (Huie et al. 1998; Sharma et al. 2005; Montalvo et al. 2006; Bali et al. 2011; Yang et al. 2011; Carlier et al. 2011; Liu et al. 2014). Control data are unavailable for this variant, but it is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. GAA activity was measured at 0.1-1.0% of normal in fibroblasts from individuals carrying the p.Arg672Trp variant (Bali et al. 2011), and was decreased in muscle and lymphocytes of individuals carrying the variant (Sharma et al. 2005; Liu et al. 2014). Based on the evidence, the p.Arg672Trp 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169099 SCV001370743 pathogenic Glycogen storage disease, type II 2020-05-29 criteria provided, single submitter clinical testing Variant summary: GAA c.2014C>T (p.Arg672Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241258 control chromosomes. c.2014C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Bali_2011, Angelini_2012, Liu_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on GAA activity. The most pronounced variant effect was estimated to be less than 10% of normal activity (Bali_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169099 SCV001417567 pathogenic Glycogen storage disease, type II 2020-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 672 of the GAA protein (p.Arg672Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs757111744, ExAC 0.008%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 9535769, 15986226). ClinVar contains an entry for this variant (Variation ID: 188773). This variant has been reported to affect GAA protein function (PMID: 9535769). This variant disrupts the p.Arg672 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23884227, 11053688, 28592009, 25712382, 9535769, 19862843). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000169099 SCV000220288 pathogenic Glycogen storage disease, type II 2018-10-19 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000169099 SCV001422655 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Arg672Trp variant in GAA has been reported in the compound heterozygous state in 11 individuals (including 3 Chinese, 2 Italian, and 1 German individuals) with Glycogen Storage Disease II (PMID: 21803581, 21484825, 25526786, 21757382, 16917947, 27692865, 22676651, 9535769) and has also been reported pathogenic by EGL Genetic Diagnostics and Illumina and likely pathogenic by Counsyl in ClinVar (Variation ID: 188773). This variant has been identified in 0.003% (1/29806) of South Asian chromosomes and 0.001% (1/108738) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757111744). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 combination with a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Arg672Trp variant is pathogenic (PMID: 9535769). A pathogenic variant at the the same position, p.Arg672Gln, has been associated with disease, supporting that a change at this position may not be tolerated (Variation ID: 371126). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on <10% of normal GAA activity in lymphocytes, muscle, or fibroblasts (PMID: 25526786, 9535769, 21484825, 22676651). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP4, PP3, PM3_Supporting (Richards 2015).

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