rs142967546

chr17-80107705-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000152.5(GAA):c.841C>T(p.Arg281Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,610,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 U:5
• Conservation: PhyloP100: 2.23

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 17-80107705-C-T is Pathogenic according to our data. Variant chr17-80107705-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283894.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.841C>T	p.Arg281Trp	missense_variant	4/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.841C>T	p.Arg281Trp	missense_variant	4/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 47 AN: 150096 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000981

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: 0.00

Gnomad NFE AF: 0.000623

Gnomad OTH AF: 0.000490

GnomAD3 exomes AF: 0.000206 AC: 51 AN: 247128 Hom.: 0 AF XY: 0.000194 AC XY: 26 AN XY: 134154

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000544 AC: 794 AN: 1460482 Hom.: 1 Cov.: 33 AF XY: 0.000546 AC XY: 397 AN XY: 726584

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000664

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000306 AC: 46 AN: 150216 Hom.: 0 Cov.: 34 AF XY: 0.000287 AC XY: 21 AN XY: 73270

Gnomad4 AFR AF: 0.0000978

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: 0.000608

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.000312 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 13, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 281 of the GAA protein (p.Arg281Trp). This variant is present in population databases (rs142967546, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Pompe disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 283894). 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%. This variant disrupts the p.Arg281 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2023	The p.Arg281Trp variant in GAA has been reported in at least 4 compound heterozygous individuals with biochemically confirmed Pompe disease and one compound heterozygous individual with sudden death under the age of 45 (Angelini 2011 PMID: 22081099, Kishnani 2019 PMID: 31086307, Salfati 2019 PMID: 31847883, Ficicoglu 2020 PMID: 33202836, ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel personal communication 2023). It has also been identified in 0.062% (42/67436) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as likely pathogenic on December 5, 2019 by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (Variation ID 283894). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PM3_Strong, PP3, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	The GAA c.841C>T; p.Arg281Trp variant (rs142967546) is reported in a carrier of Pompe disease identified by newborn screening (Wittmann 2012) and in an individual with suspected late onset Pompe disease who carried a second GAA variant (Ficicioglu 2020). The p.Arg281Trp variant is classified as likely pathogenic by an expert panel in ClinVar (Variation ID: 283894). It is found in the general population with an overall allele frequency of 0.02% (57/277866 alleles) in the Genome Aggregation Database. The arginine at codon 281 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.786). Based on available information, this variant is considered to be likely pathogenic. References: Ficicioglu C et al. Newborn Screening for Pompe Disease: Pennsylvania Experience. Int J Neonatal Screen. 2020 Nov 13;6(4):89. PMID: 33202836. Wittmann J et al. Newborn screening for lysosomal storage disorders in hungary. JIMD Rep. 2012;6:117-25. PMID: 23430949. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 05, 2019	This variant, c.841C>T (p.Arg281Trp), has been identified by a clinical diagnostic laboratory in three individuals who meets the ClinGen LSD VCEP's specifications for PP4_Moderate. All three individuals are compound heterozygous for the variant and a pathogenic variant in GAA; either c.2481+102_2646+31del (phase unknown), c.172C>T (p.Gln58Ter) (phase unknown), or c.2161delG (confirmed in trans). This data meets PM3_Strong. In addition, the variant was reported in a patient with late onset Pompe disease with no second variant identified (PMID 22081099), and a heterozygous individual identified on newborn screen (PMID 23430949). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894; 2 star review status) with 4 submitters all classifying the variant as a variant of uncertain significance. However, based on the unpublished clinical laboratory data available, this variant meets the criteria to the classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met: PM2, PM3_Strong, PP3, PP4_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2023	Variant summary: GAA c.841C>T (p.Arg281Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of 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 0.00021 in 247128 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.841C>T has been reported in the literature in individuals affected with Glycogen Storage Disease (examples: Angelini_2012, Liao_2017, Kishnani_2019, Ficicioglu_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters (including ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -

not provided Pathogenic:4 Uncertain:3

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 17, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	PP3, PP4_moderate, PM2, PM3_very_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	Identified in an individual with late-onset Pompe disease with significant residual GAA activity in muscle; a second variant in the GAA gene was not identified in this individual (Angelini et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 283894; ClinVar); This variant is associated with the following publications: (PMID: 33560568, 33202836, 34356580, 19343043, 22081099, 31086307, 23430949, 33717985, 33073009, 33073027) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	GAA: PM3:Strong, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.66	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95
MVP		1.0
MPC		0.55
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142967546; hg19: chr17-78081504; COSMIC: COSV56409042; COSMIC: COSV56409042;