rs747610090

chr17-80108818-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1316T>A(p.Met439Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,441,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M439I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.49

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-80108818-T-A is Pathogenic according to our data. Variant chr17-80108818-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 371305.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108818-T-A is described in Lovd as [Likely_pathogenic]. Variant chr17-80108818-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1316T>A	p.Met439Lys	missense_variant	8/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1316T>A	p.Met439Lys	missense_variant	8/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000284 AC: 6 AN: 210934 Hom.: 0 AF XY: 0.0000348 AC XY: 4 AN XY: 114784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000384

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1441610 Hom.: 0 Cov.: 36 AF XY: 0.00000699 AC XY: 5 AN XY: 715714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000233

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 03, 2022	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. -

Glycogen storage disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 12, 2017

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) -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Benign	0.0083
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.096	B;B
Vest4		0.91
MutPred		0.91		Loss of stability (P = 0.0308);Loss of stability (P = 0.0308);
MVP		0.99
MPC		0.20
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747610090; hg19: chr17-78082617; COSMIC: COSV100163128; COSMIC: COSV100163128;