ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1222A>G (p.Met408Val) (rs560575383)

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Total submissions: 4
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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 RCV000410896 SCV001371760 likely pathogenic Glycogen storage disease, type II 2020-04-06 reviewed by expert panel curation This variant, 1222A>G, (p.Met408Val), is a missense substitution which has been reported in two individuals with infantile onset Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. One of these patients is homozygous for the variant (PMID 26497565). The other patient is compound heterozygous for the variant and c.1408_1410del (p.Asn470del) (PMID 11738358); however, this in trans data was used in the assessment of p.Asn470del, and will not be used here in order to avoid circular logic. Based on this data, PM3_Supporting is met. When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843), meeting PS3. The score for the REVEL in silico predictor, 0.637, meets neither PP3 nor BP4. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied: PS3, PM2, PM3_Supporting, PP4.
Counsyl RCV000410896 SCV000486766 likely pathogenic Glycogen storage disease, type II 2016-08-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410896 SCV001362546 pathogenic Glycogen storage disease, type II 2019-11-01 criteria provided, single submitter clinical testing Variant summary: GAA c.1222A>G (p.Met408Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248202 control chromosomes (gnomAD). c.1222A>G has been reported in the literature in homozygous or compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Fernandez-Hojas_2002, Gort_2007, Labrousse_2010, Manwaring_2012, Broomfield_2016). These data indicate that the variant is likely to be associated with disease. The variant protein was reported to have less than 2% GAA activity in an in vitro expression system (Flanagan_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000410896 SCV001422624 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Met408Val variant in GAA has been reported in 5 individuals (including 2 Spanish, 2 from the UK, and 1 Taiwanese) with Glycogen Storage Disease II (PMID: 11738358, 21687968, 17616415, 26497565, 20080426), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 371235). This variant has been identified in 0.002% (2/111716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs560575383). 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 COS cells transfected with this variant provide some evidence that the p.Met408Val variant may impact GAA activity (PMID: 19862843). 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 Methionine (Met) at position 408 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Met408Val variant is pathogenic (PMID: 26497565). The phenotype of an individual homozygous and 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormal GAA activity assay results in relevant tissues (PMID: 26497565, 17616415, 11738358). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP4, PM3_Supporting (Richards 2015).

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