rs1555600061

Positions:

• chr17-80108512-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PM3_Strong PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1099T>C (p.Trp367Arg) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.0000013 (1/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been reported in at least 3 patients with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and/or on enzyme replacement therapy (ERT) (PMID:17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient of late-onset Pompe disease (LOPD) (PMID:22958975) (PP4_Moderate). This variant was found to be homozygous in one Spanish-Italian patient with IOPD and was confirmed to be inherited from both parents (PMID:17056254). At least one Hispanic patient with IOPD under ERT (PMID:22658377, 23787031, 25139343) was found to be compound heterozygous (phase unknown) for this variant and c.1802C>T (p.Ser601Leu), a GAA variant classified as pathogenic by the ClinGen LD VCEP. This variant was confirmed to be in trans with c.1942G>A (p.Gly648Ser), a GAA variant classified as pathogenic by the ClinGen LD VCEP, in a Thailand patient with IOPD (PMID:31510962). One Italian patient with LOPD was reported to be compound heterozygous (phase unknown) for the variant and c.-32-13T>G, the most common pathogenic GAA variant associated with LOPD (PMID:22958975) (PM3_Strong). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID:19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID:29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LD VCEP, on December 5, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401364951/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.50

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 Likely_pathogenic. Variant got 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1099T>C	p.Trp367Arg	missense_variant	7/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1099T>C	p.Trp367Arg	missense_variant	7/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460828 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 726736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant summary: GAA c.1099T>C (p.Trp367Arg) 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 was absent in 244902 control chromosomes (gnomAD). c.1099T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), including a homozygous patient (Palmer 2007, Palermo 2012, Musumeci 2012, Mori 2017). These data indicate that the variant is likely to be associated with disease. One of these publications also reported that GAA enzyme activity levels measured from a dried blood spot were outside the range of normal activity in a homozygous patient (Palmer 2007). At least one other publication reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <2% of normal activity (Flanagan 2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 05, 2023	The NM_000152.5: c.1099T>C (p.Trp367Arg) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.0000013 (1/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been reported in at least 3 patients with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and/or on enzyme replacement therapy (ERT) (PMID: 17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient of late-onset Pompe disease (LOPD) (PMID: 22958975) (PP4_Moderate). This variant was found to be homozygous in one Spanish-Italian patient with IOPD and was confirmed to be inherited from both parents (PMID: 17056254). At least one Hispanic patient with IOPD under ERT (PMID: 22658377, 23787031, 25139343) was found to be compound heterozygous (phase unknown) for this variant and c.1802C>T (p.Ser601Leu), a GAA variant classified as pathogenic by the ClinGen LD VCEP. This variant was confirmed to be in trans with c.1942G>A (p.Gly648Ser), a GAA variant classified as pathogenic by the ClinGen LD VCEP, in a Thailand patient with IOPD (PMID: 31510962). One Italian patient with LOPD was reported to be compound heterozygous (phase unknown) for the variant and c.-32-13T>G, the most common pathogenic GAA variant associated with LOPD (PMID: 22958975) (PM3_Strong). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID: 19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID: 29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LD VCEP, on December 5, 2023). -
Uncertain significance, flagged submission	clinical testing	Counsyl	Dec 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 367 of the GAA protein (p.Trp367Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 17056254, 22958975, 23787031, 31510962). 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: 555820). 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: 19862843). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-14	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.96		Gain of methylation at W367 (P = 0.0123);Gain of methylation at W367 (P = 0.0123);
MVP		1.0
MPC		0.72
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.98

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: rs1555600061; hg19: chr17-78082311;