ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1309C>T (p.Arg437Cys) (rs770610356)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169488 SCV000220942 likely pathogenic Glycogen storage disease, type II 2014-12-10 criteria provided, single submitter literature only
Invitae RCV000169488 SCV000931738 pathogenic Glycogen storage disease, type II 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 437 of the GAA protein (p.Arg437Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs770610356, ExAC 0.004%). This variant has been observed as homozygous or in combination with another GAA variant in individuals affected with glycogen storage disease (PMID: 12601120, 17805474, 29124014) including one individual in whom another pathogenic variant was observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with glycogen storage disease (PMID: 12601120). 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: 189082). Experimental studies have shown that this missense change abrogates GAA activity (PMID: 12601120). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197848 SCV001368628 likely pathogenic Elevated serum creatine phosphokinase; Cerebellar ataxia; Generalized hypotonia; Delayed gross motor development; Difficulty walking; Poor speech 2019-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BS2,BS6. This variant was detected in heterozygous state.
Integrated Genetics/Laboratory Corporation of America RCV000169488 SCV001370551 pathogenic Glycogen storage disease, type II 2020-05-05 criteria provided, single submitter clinical testing Variant summary: GAA c.1309C>T (p.Arg437Cys) 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 4.6e-06 in 217456 control chromosomes. c.1309C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of wild-type enzyme activity (Tajima_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics,Johns Hopkins University RCV000169488 SCV001425407 pathogenic Glycogen storage disease, type II 2020-05-21 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000169488 SCV001422625 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg437Cys variant in GAA has been reported in 13 individuals (including 7 Japanese, 3 Chinese, and 2 Korean) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 18495398, 22521436, 12601120, 23884227, 24169249, 25388776, 21984055, 25526786, 17805474, 24190153, 24872213, 21704464), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 189082). This variant has been identified in 0.009% (2/21914) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770610356). 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 a minigene assay provide some evidence that the p.Arg437Cys variant may impact GAA activity and levels (PMID: 19862843). 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. However, the Arginine (Arg) at position 437 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg437Cys variant is pathogenic (PMID: 22521436, 12601120, 17805474). One additional variant at the same position, p.Arg437His, has been reported as a VUS in ClinVar (Variation ID: 456374). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity, consistent with disease (PMID: 12601120, 17805474, 22521436). 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 evidence from in vitro functional studies. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, PP4 (Richards 2015).

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