ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000169620 SCV001371775 pathogenic Glycogen storage disease, type II 2020-05-03 reviewed by expert panel curation This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763C > T (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP4.
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.
Broad Institute Rare Disease Group,Broad Institute RCV000169620 SCV001422667 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Arg224Trp variant in GAA has been reported in the compound heterozygous state in 6 individuals with Glycogen Storage Disease II (PMID: 25673129, 12923862, 25026126, 23632174, 14643388), and has been identified 0.005% (6/127580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757700700). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by EGL Genetic Diagnostics, a likely pathogenic variant by Counsyl, and a pathogenic variant by Invitae and Integrated Genetics in ClinVar (Variation ID: 189188). In vitro functional studies provide some evidence that the p.Arg224Trp variant may impact GAA activity (PMID: 19862843, 14643388, 12923862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg224Trp variant is pathogenic (PMID: 12923862, 25673129, 25026126). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP4 (Richards 2015).

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