ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1979G>A (p.Arg660His) (rs374143224)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169600 SCV000221116 likely pathogenic Glycogen storage disease, type II 2015-02-04 criteria provided, single submitter literature only
GeneDx RCV000256037 SCV000322397 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The R660H pathogenic variant in the GAA gene has been reported previously in glycogen storage disease type II, in multiple affected individuals who were also reported with a second GAA variant (Pipo et al., 2003; Bernstein et al., 2010; Burrow et al., 2010; Palermo et al., 2012). Additionally, studies in COS cells with the R660H variant show that this variant impacts the function of the protein (Pipo et al., 2003). The R660H variant was not observed in the homozygous state or at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The R660H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R660H as a pathogenic variant.
Invitae RCV000169600 SCV000626537 pathogenic Glycogen storage disease, type II 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 660 of the GAA protein (p.Arg660His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs374143224, ExAC 0.04%). This variant has been reported in the compound heterozygous or homozygous state in several individuals affected with Pompe disease and an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 14643388, 27649523, 20472203, 21484825, 22555271, 22521436). In addition, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Pompe disease (PMID: 20638881). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 189172). Experimental studies have shown that this missense change reduces enzyme activity to less than 10% of wild-type (PMID: 14643388). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000256037 SCV000706386 pathogenic not provided 2017-02-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000169600 SCV000894163 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169600 SCV000917390 pathogenic Glycogen storage disease, type II 2018-03-09 criteria provided, single submitter clinical testing Variant summary: GAA c.1979G>A (p.Arg660His) 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 0.00013 in 31000 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Pipo_2003, Bernstein_2010, Bali_2011). These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on enzyme activity (Pipo_2003, Bali_2011). The most pronounced variant effect results in <10% of normal activity. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000256037 SCV001245692 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000169600 SCV001133216 likely pathogenic Glycogen storage disease, type II 2019-09-26 no assertion criteria provided clinical testing

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