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

gnomAD frequency: 0.00003  dbSNP: rs747610090

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000410956	SCV002540669	pathogenic	Glycogen storage disease, type II	2022-06-03	reviewed by expert panel	curation	The NM_000152.5:c.1316T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 439 (p.Met439Lys). At least 14 patients have been reported with this variant and features consistent with Pompe disease. This includes 7 patients with documented laboratory values showing deficiency of GAA activity, below the reference range for normal activity in leukocytes (PMIDs: 17092519, 21940687, 23884227, 25388776, 28433475, 30360039), some of whom are also reported to have histological features of Pompe disease in muscle (PMID: 20202878, 30894207), and/or documented features of infantile onset Pompe disease including muscle weakness and cardiomyoapthy (PMID: 33344388) and/or on enzyme replacement therapy (PMID: 30894207, 31193175) (PP4_Moderate). Note that pseudodeficiency variants, (p.Gly576Ser and p.Glu689Lys) were confirmed to be absent in at least one of these cases (PMID 28433475). Of these patients, 7 are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.1798C>T (p.Arg600Cys) (PMID: 20202878; phase unknown, 0.5 points), c.2238G>C (p.Trp746Cys) (PMID: 30894207, confirmed in trans, 1 point) (PMID: 25388776, unknown phase, 0.5 points), c.546G>T (PMID: 28433475, unknown phase, 0.5 points), c.2407_2413del (p.Gln803Ter) (PMID: 23884227, unknown phase, 0.5 points), and c.1579_1580del (p.Arg527GlyfsTer3) (PMID: 30360039, phase unknown, 0.5 points), and c.1225dup (PMID: 29869463; phase unknown, 0.25 points); and one patient is homozygous (PMID: 29124014) (0.5 points). Total 4.25 points (PM3_VeryStrong). Additional patients have been reported who are compound heterozygous for the variant and c.796C>T (p.Pro266Ser) (PMID: 17092519, 29044175, 31850350), c.1225dup (PMID: 29869463), and c.1309C>T (p.Arg437Cys) (PMID: 25388776) but the allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Additional data was not included due to uncertainty about the nomenclature of the second variant (PMIDs: 20202878, 21940687). The highest population minor allele frequency in gnomAD is 0.00038 (6/15644 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells the variant has <2% normal activity and does not show mature GAA protein on western blot (PMID 19862843) (PM3_Moderate). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 371305, 2 star review status) with 3 submitters classifying the variant as pathogenic and 4 as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications version 2): PM3_VeryStrong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022.
Counsyl	RCV000410956	SCV000486855	likely pathogenic	Glycogen storage disease, type II	2016-08-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-11-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 371305). This missense change has been observed in individual(s) with Pompe disease (PMID: 17092519, 20202878, 23884227, 25213570, 29124014). This variant is present in population databases (rs747610090, gnomAD 0.04%). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 439 of the GAA protein (p.Met439Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000410956	SCV001422942	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410956	SCV001983409	pathogenic	Glycogen storage disease, type II	2021-09-06	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1316T>A (p.Met439Lys) results in a non-conservative amino acid change located in the Glycoside hydrolase, family 31 domain (IPR000322) 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 2.8e-05 in 210934 control chromosomes. c.1316T>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Park_2006, Kobayashi_2010, Park_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Flanagan_2009). The most pronounced variant effect results in <2% of normal wild-type GAA activity in transiently transfected COS-7 cells. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001782875	SCV002025199	likely pathogenic	not provided	2021-06-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410956	SCV004197815	pathogenic	Glycogen storage disease, type II	2023-06-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000410956	SCV002092012	pathogenic	Glycogen storage disease, type II	2020-01-28	no assertion criteria provided	clinical testing