rs786204680

chr17-80108811-C-Tchr17-80108811-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1309C>T(p.Arg437Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,598,124 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. R437H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.49

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80108811-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2155070.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-80108811-C-T is Pathogenic according to our data. Variant chr17-80108811-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189082.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108811-C-T is described in Lovd as [Pathogenic]. Variant chr17-80108811-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1309C>T	p.Arg437Cys	missense_variant	8/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1309C>T	p.Arg437Cys	missense_variant	8/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000460 AC: 1 AN: 217456 Hom.: 0 AF XY: 0.00000845 AC XY: 1 AN XY: 118356

Gnomad AFR exome AF: 0.0000757

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000830 AC: 12 AN: 1445940 Hom.: 0 Cov.: 36 AF XY: 0.00000835 AC XY: 6 AN XY: 718182

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 437 of the GAA protein (p.Arg437Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 12601120, 17805474, 29124014). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189082). 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) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 12601120). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 10, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg437Cys variant in GAA has been reported in 13 individuals (including 7 Japanese, 3 Chinese, and 2 Korean) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 18495398, 22521436, 12601120, 23884227, 24169249, 25388776, 21984055, 25526786, 17805474, 24190153, 24872213, 21704464), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 189082). This variant has been identified in 0.009% (2/21914) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770610356). 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 a minigene assay provide some evidence that the p.Arg437Cys variant may impact GAA activity and levels (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. However, the Arginine (Arg) at position 437 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg437Cys variant is pathogenic (PMID: 22521436, 12601120, 17805474). One additional variant at the same position, p.Arg437His, has been reported as a VUS in ClinVar (Variation ID: 456374). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity, consistent with disease (PMID: 12601120, 17805474, 22521436). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with pathogenic and likely pathogenic variants in individuals with Glycogen Storage Disease II and evidence from in vitro functional studies. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2020	Variant summary: GAA c.1309C>T (p.Arg437Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-06 in 217456 control chromosomes. c.1309C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). 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. The most pronounced variant effect results in <10% of wild-type enzyme activity (Tajima_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 21, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 30, 2022	The NM_000152.5:c.1309C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 437 (p.Arg437Cys). This variant has been reported in at least 16 East Asian individuals with late onset Pompe disease (PMID: 34356580) including 11 individuals with documented laboratory values reporting GAA activity <10% normal in muscle or skin fibroblasts or in the affected range in a clinically validated dried blood spot assay and/or histological features consistent with Pompe disease in muscle, and/or on enzyme replacement therapy for Pompe disease (PMID 22521436, 29786057, 27692865, 30360039)(PP4_Moderate). Ten individuals are reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including one confirmed in trans, c.1082C>T (p.Pro361Leu) (PMID: 12601120), and 9 phase unknown, c.796C>T (p.Pro266Ser) (PMID: 25526786), c.1082C>T (p.Pro361Leu) (PMID: 27692865), c.1316T>A (p.Met439Lys) (PMID: 25388776), c.1822C>T (p.Arg608Ter) (PMID: 30360039), c.1978C>T (p.Arg600Cys) (PMID: 29124014, 3 probands), c.2238G>C (p.Trp746Cys) (PMID: 27692865), c.2297A>G (p.Tyr766Cys) (PMID: 29124014) (PM3_VeryStrong). The variant has also been reported in compound heterozygosity with c.1544T>A (p.Met515Lys) (PMID: 24190153), c.1562A>T (p.Glu521Val) (PMID: 29786057), c.1857C>G (p.Ser619Arg) (PMID: 291240140, c.2051C>A (p.Pro684Gln) (PMID: 29451150), c.2177C>G (p.Pro726Arg) (PMID: 29124014), and c.2297A>C (p.Tyr766Ser) (PMID: 22521436). The allelic data from these patients will be used in the classification of the second variant and is not included here in order to avoid circular logic. Additional patients have also been reported but the data was not included because the cDNA sequences of the variants was not included (PMID: 18495398, 21471980, 21704464). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (2/21914 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cells showed no detectable GAA enzyme activity, and another study showed abnormal synthesis and processing of GAA when the variant was expressed in COS cells, indicating that this variant may impact protein function (PMID: 12601120, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.782, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A novel variant at the same amino acid position, c.1310G>A (p.Arg437His) has been reported in a patient with Pompe disease (PMID: 25681614) but has not yet been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, PM5 is not applied. There is a ClinVar entry for this variant (Variation ID: 189082, 2 star review status) with 6 submitters classifying the variant as pathogenic and two as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2022	Published functional studies with this variant showed no detectable GAA activity in Ad5-SV40 immortalized human GAA-deficient fibroblast cells and abnormal processing and synthesis of GAA when expressed in COS cells (Lam et al., 2003; Flanagan et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23884227, 21471980, 12601120, 21704464, 27692865, 24190153, 24169249, 21984055, 29124014, 29451150, 30281819, 25526786, 24872213, 18495398, 21940687, 25388776, 17805474, 22521436, 11053688, 22253258, 19343043, 34405923, 34922579, 19862843) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.62
MutPred		0.89		Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);
MVP		1.0
MPC		0.56
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.82
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770610356; hg19: chr17-78082610;