rs757700700

chr17-80105872-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.670C>T(p.Arg224Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,599,354 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. R224Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1 O:1
• Conservation: PhyloP100: -0.0370

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80105873-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 664582.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 17-80105872-C-T is Pathogenic according to our data. Variant chr17-80105872-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189188.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80105872-C-T is described in Lovd as [Pathogenic]. Variant chr17-80105872-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-80105872-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.670C>T	p.Arg224Trp	missense_variant	3/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.670C>T	p.Arg224Trp	missense_variant	3/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000205 AC: 5 AN: 243354 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132516

Gnomad AFR exome AF: 0.00

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: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 36 AN: 1447026 Hom.: 0 Cov.: 34 AF XY: 0.0000236 AC XY: 17 AN XY: 719062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000307

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 03, 2020	This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763C > T (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the 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: PS3, PM2, PM3_Strong, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2018	Variant summary: GAA c.670C>T (p.Arg224Trp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel 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 2.2e-05 in 269992 control chromosomes (gnomAD and publications). The variant, c.670C>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Habbal_2013, Pipo_2003, Pittis_2003, Pittis_2008). These data indicate that the variant is likely to be associated with disease. Multiple publications have functionally assessed the variant indicating the variant significantly impedes GAA enzymatic activity (Angelini_2012, Pipo_2003, Pittis_2003). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic or uncertain significance without additional evidence to independently evaluate. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2022	The GAA c.670C>T (p.Arg224Trp) missense variant results in the substitution of arginine at amino acid position 224 with tryptophan. Across a selection of the available literature, the c.670C>T variant has been identified in a compound heterozygous state in at least six individuals affected with glycogen storage disease, type II (Pipo et al. 2003; Pittis et al. 2003; Zouheir Habbal et al. 2013; Aykut et al. 2014; Parini et al. 2018). Affected individuals show reduced alpha-glucosidase activity and onset of the disease is influenced by the second pathogenic variant found in trans. The c.670C>T variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000047 in the European (non-Finnish) population (version 2.1.1). Functional studies demonstrated that when the c.670C>T variant protein was expressed in cells, glucosidase enzyme activity was reduced to 2-10% of wild-type activity (Pittis et al. 2003; Pipo et al. 2003; Flanagan et al. 2009). Based on the available evidence, the c.670C>T (p.Arg224Trp) variant is classified as pathogenic for glycogen storage disease, type II. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the GAA protein (p.Arg224Trp). This variant is present in population databases (rs757700700, gnomAD 0.004%). This missense change has been observed in individuals with Pompe disease (PMID: 12923862, 14643388, 18429042, 25026126, 29422078). ClinVar contains an entry for this variant (Variation ID: 189188). 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: 12923862, 14643388, 19862843). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 04-29-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Arg224Trp variant in GAA has been reported in the compound heterozygous state in 6 individuals with Glycogen Storage Disease II (PMID: 25673129, 12923862, 25026126, 23632174, 14643388), and has been identified 0.005% (6/127580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757700700). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by EGL Genetic Diagnostics, a likely pathogenic variant by Counsyl, and a pathogenic variant by Invitae and Integrated Genetics in ClinVar (Variation ID: 189188). In vitro functional studies provide some evidence that the p.Arg224Trp variant may impact GAA activity (PMID: 19862843, 14643388, 12923862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg224Trp variant is pathogenic (PMID: 12923862, 25673129, 25026126). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 29, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;D
Eigen	Benign	-0.0013
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.50	D
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.60	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92, 0.93
MutPred		0.87		Gain of catalytic residue at Q225 (P = 0.057);Gain of catalytic residue at Q225 (P = 0.057);Gain of catalytic residue at Q225 (P = 0.057);
MVP		0.98
MPC		0.55
ClinPred		1.0	D
GERP RS		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs757700700; hg19: chr17-78079671;