chr17-80113001-C-T

Position:

chr17-80113001-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PM2_SupportingPM3_StrongPM5_SupportingPS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2014C>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 672 (p.Arg672Trp). The variant has been reported in 5 patients with a diagnosis of Pompe disease supported by <10% normal GAA activity in muscle (PMID 9535769), <1% GAA activity in cultured fibroblasts (PMID 16917947), or GAA activity in the affected range in leukocytes or lymphocytes (PMID 22676651, 25526786) in addition to at least 5 patients stated to have symptoms consistent with Pompe disease and deficient GAA activity but values not provided (PMID 16917947, 21803581, 27692865)(PP4_Moderate). At least 5 patients are compound heterozygous for the variant and a variant in GAA classified as pathogenic by the ClinGen LSD VCEP, phase unknown - c.-32-13T>G (PMID 16917947), c.2385delG (PMID 21484825), c.1411_1414del (PMID 27692865), c.766_785delinsC (PMID 9535769), and c.1951_1952insT (clinical laboratory data) (PM3_Strong). The variant has also been reported in compound heterozygotes with c.1748C>T(p.Ser583Phe)(PMID 21484825), c.323G>A (p.Cys108Tyr) (PMID 25526786), c.1465G>A (p.Asp489Asn)(PMID 16917947), c.1703A>T (p.His568Leu)(PMID 17027861, 22676651), c.2474C>G (p.Pro825Arg)(PMID 30564623). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/29806 alleles) in the South Asian 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 SV40-immortalized GAA-deficient fibroblasts revealed activity of <1% of the control value (PMID 9535769), and <2% activity in COS cells (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.9 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2015G>A (p.Arg672Gln)(see Table 1 in PMID 33578445) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (likely pathogenic without PM5 data from c.2014C>T (p.Arg672Trp) PM5_Supporting). c.2015G>T (p.Arg672Leu) has also been reported but has not yet met the criteria to be classified as pathogenic or likely pathogenic. There is a ClinVar entry for this variant (Variation ID: 188773; 2 star status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP: PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273939/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 0.949

Variant links:

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]

GAA links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3

PM2

PM3

PM5

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2014C>T	p.Arg672Trp	missense_variant	14/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2014C>T	p.Arg672Trp	missense_variant	14/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000829

AC:

AN:

241258

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131614

show subpopulations

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:

0.0000336

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000892

AC:

AN:

1458210

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725260

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Bravo

AF:

0.00000756

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 672 of the GAA protein (p.Arg672Trp). 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: 9535769, 15986226). ClinVar contains an entry for this variant (Variation ID: 188773). 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: 9535769). This variant disrupts the p.Arg672 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 11053688, 19862843, 23884227, 25712382, 28592009). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2020	Variant summary: GAA c.2014C>T (p.Arg672Trp) 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 8.3e-06 in 241258 control chromosomes. c.2014C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Bali_2011, Angelini_2012, Liu_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on GAA activity. The most pronounced variant effect was estimated to be less than 10% of normal activity (Bali_2011). Three 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 04, 2022	The NM_000152.5:c.2014C>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 672 (p.Arg672Trp). The variant has been reported in 5 patients with a diagnosis of Pompe disease supported by <10% normal GAA activity in muscle (PMID 9535769), <1% GAA activity in cultured fibroblasts (PMID 16917947), or GAA activity in the affected range in leukocytes or lymphocytes (PMID 22676651, 25526786) in addition to at least 5 patients stated to have symptoms consistent with Pompe disease and deficient GAA activity but values not provided (PMID 16917947, 21803581, 27692865)(PP4_Moderate). At least 5 patients are compound heterozygous for the variant and a variant in GAA classified as pathogenic by the ClinGen LSD VCEP, phase unknown - c.-32-13T>G (PMID 16917947), c.2385delG (PMID 21484825), c.1411_1414del (PMID 27692865), c.766_785delinsC (PMID 9535769), and c.1951_1952insT (clinical laboratory data) (PM3_Strong). The variant has also been reported in compound heterozygotes with c.1748C>T(p.Ser583Phe)(PMID 21484825), c.323G>A (p.Cys108Tyr) (PMID 25526786), c.1465G>A (p.Asp489Asn)(PMID 16917947), c.1703A>T (p.His568Leu)(PMID 17027861, 22676651), c.2474C>G (p.Pro825Arg)(PMID 30564623). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/29806 alleles) in the South Asian 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 SV40-immortalized GAA-deficient fibroblasts revealed activity of <1% of the control value (PMID 9535769), and <2% activity in COS cells (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.9 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2015G>A (p.Arg672Gln)(see Table 1 in PMID 33578445) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (likely pathogenic without PM5 data from c.2014C>T (p.Arg672Trp) PM5_Supporting). c.2015G>T (p.Arg672Leu) has also been reported but has not yet met the criteria to be classified as pathogenic or likely pathogenic. There is a ClinVar entry for this variant (Variation ID: 188773; 2 star status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP: PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The GAA c.2014C>T (p.Arg672Trp) variant was identified in a compound heterozygous state in at least 11 individuals with late-onset glycogen storage disease type II (Huie et al. 1998; Sharma et al. 2005; Montalvo et al. 2006; Bali et al. 2011; Yang et al. 2011; Carlier et al. 2011; Liu et al. 2014). Control data are unavailable for this variant, but it is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. GAA activity was measured at 0.1-1.0% of normal in fibroblasts from individuals carrying the p.Arg672Trp variant (Bali et al. 2011), and was decreased in muscle and lymphocytes of individuals carrying the variant (Sharma et al. 2005; Liu et al. 2014). Based on the evidence, the p.Arg672Trp variant is classified as pathogenic for glycogen storage disease type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Arg672Trp variant in GAA has been reported in the compound heterozygous state in 11 individuals (including 3 Chinese, 2 Italian, and 1 German individuals) with Glycogen Storage Disease II (PMID: 21803581, 21484825, 25526786, 21757382, 16917947, 27692865, 22676651, 9535769) and has also been reported pathogenic by EGL Genetic Diagnostics and Illumina and likely pathogenic by Counsyl in ClinVar (Variation ID: 188773). This variant has been identified in 0.003% (1/29806) of South Asian chromosomes and 0.001% (1/108738) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757111744). 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 suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Arg672Trp variant is pathogenic (PMID: 9535769). A pathogenic variant at the the same position, p.Arg672Gln, has been associated with disease, supporting that a change at this position may not be tolerated (Variation ID: 371126). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on <10% of normal GAA activity in lymphocytes, muscle, or fibroblasts (PMID: 25526786, 9535769, 21484825, 22676651). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP4, PP3, PM3_Supporting (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

1.0

MutPred

0.98

Loss of disorder (P = 0.0422);Loss of disorder (P = 0.0422);

MVP

1.0

MPC

0.55

ClinPred

1.0

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over