ClinVar Miner

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

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Total submissions: 3
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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
Invitae RCV000410956 SCV000954422 pathogenic Glycogen storage disease, type II 2018-08-14 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.
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,; 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)

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