ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1316T>A (p.Met439Lys) (rs747610090)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410956 SCV000486855 likely pathogenic Glycogen storage disease, type II 2016-08-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612594 SCV000731983 likely pathogenic Glycogen storage disease 2017-10-12 criteria provided, single submitter clinical testing The p.Met439Lys (NM_001079803.1 c.1316T>A) variant in GAA has been reported in a t least 10 compound heterozygous individuals with Pompe disease and segregated w ith disease in one affected sibling (Park 2006, Kobayashi 2010, Park 2013, Lee 2 014, Lee 2017 and Park 2017). This variant has also been reported in ClinVar (Va riation ID#371305), as likely pathogenic. In vitro functional studies provide ev idence that the variant impairs enzymatic activity (Flanagan 2009). This varian t has been identified in 6/14,598 of East Asian chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs747610090), th ough this frequency is low enough to be consistent with a recessive carrier freq uency. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Met439Lys variant is likely pathogenic for Pompe disease in an autosomal recessive manner based upon observations in affected in dividuals and functional studies. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP5 (Richards 2015)
Invitae RCV000410956 SCV000954422 pathogenic Glycogen storage disease, type II 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 439 of the GAA protein (p.Met439Lys). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is present in population databases (rs747610090, ExAC 0.06%). This variant has been observed to be homozygous or in combination with another GAA variant in individuals affected with Pompe disease (PMID: 17092519, 25213570, 20202878, 23884227, 29124014). ClinVar contains an entry for this variant (Variation ID: 371305). Experimental studies have shown that this missense change results in a GAA protein with less than 2% wild-type enyzme activity (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000410956 SCV001422942 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Met439Lys variant in GAA has been reported in 6 Korean individuals with Glycogen Storage DIsease II, segregated with disease in 2 affected siblings from 1 family (PMID: 17092519, 25213570, 28433475, 27363342), and has also been reported a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and the Laboratory for Molecular Medicine by ClinVar (Variation ID: 371305). This variant has been identified in 0.038% (6/15644) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747610090). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, the Methionine (Met) at position 439 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Met439Lys variant may impact GAA activity (PMID: 19862843). However, these types of assays may not accurately represent biological function. This variant was reported in combination with variants associated with disease and in individuals with Glycogen Storage Disease II (PMID: 25213570, 27363342, 28433475). At least one individual with this variant in the heterozygous state has a phenotype highly specific for Glycogen Storage Disease II based on GAA enzyme activity assays with leukocytes and lacks two known pseudodeficiency alleles, p.Gly576Ser and Glu689Lys, raising the likelihood that this variant is pathogenic (PMID: 28433475). 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_Moderate (Richards 2015).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.