ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.670C>T (p.Arg224Trp) (rs757700700)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169620 SCV000221147 likely pathogenic Glycogen storage disease, type II 2015-02-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000272542 SCV000339005 uncertain significance not provided 2016-11-07 criteria provided, single submitter clinical testing
Invitae RCV000169620 SCV000831593 pathogenic Glycogen storage disease, type II 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 224 of the GAA protein (p.Arg224Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs757700700, ExAC 0.005%). This variant has been reported in several individuals affected with Pompe disease (PMID: 18429042, 14643388, 12923862, 25026126, 29422078). ClinVar contains an entry for this variant (Variation ID: 189188). Experimental studies have shown that this missense change causes reduced GAA activity (PMID: 12923862, 14643388, 19862843). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169620 SCV000919382 pathogenic Glycogen storage disease, type II 2018-06-04 criteria provided, single submitter clinical testing Variant summary: GAA c.670C>T (p.Arg224Trp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 269992 control chromosomes (gnomAD and publications). The variant, c.670C>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Habbal_2013, Pipo_2003, Pittis_2003, Pittis_2008). These data indicate that the variant is likely to be associated with disease. Multiple publications have functionally assessed the variant indicating the variant significantly impedes GAA enzymatic activity (Angelini_2012, Pipo_2003, Pittis_2003). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic or uncertain significance without additional evidence to independently evaluate. Based on the evidence outlined above, the variant was classified as pathogenic.
GenomeConnect, ClinGen RCV000169620 SCV001338892 not provided Glycogen storage disease, type II no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 04-29-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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