ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1843G>A (p.Gly615Arg) (rs549029029)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169115 SCV000220317 likely pathogenic Glycogen storage disease, type II 2014-05-14 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169115 SCV000919384 pathogenic Glycogen storage disease, type II 2018-07-05 criteria provided, single submitter clinical testing Variant summary: GAA c.1843G>A (p.Gly615Arg) 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 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169115 SCV000824487 pathogenic Glycogen storage disease, type II 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 615 of the GAA protein (p.Gly615Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs549029029, ExAC 0.03%). This variant has been observed to be homozygous, or in combination with another GAA variant, in several individuals affected with Pompe disease (PMID: 15366815, 10338092, 16860134, 18607768, 18458862, 21757382, 24269976, 25037089). ClinVar contains an entry for this variant (Variation ID: 188786). Experimental studies have shown that this missense change leads to reduced GAA activity in vitro (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic.

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