rs61736895

Positions:

• chr17-80117723-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID:33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID:22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815746/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:6
• Conservation: PhyloP100: 2.30

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2455C>T	p.Arg819Trp	missense_variant	17/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2455C>T	p.Arg819Trp	missense_variant	17/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 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: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000247 AC: 6 AN: 243096 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000879

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: 0.0000185

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000391 AC: 57 AN: 1459040 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 725742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 20, 2023	The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID: 33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID: 22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 819 of the GAA protein (p.Arg819Trp). This variant is present in population databases (rs61736895, gnomAD 0.009%). This missense change has been observed in individual(s) with Pompe disease (PMID: 33741225). ClinVar contains an entry for this variant (Variation ID: 456402). 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.Arg819 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	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: 19343043, 22253258, 33741225) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 04, 2023

Variant summary: GAA c.2455C>T (p.Arg819Trp) 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 2.5e-05 in 243096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2455C>T has been reported in the literature in an individual affected with Glycogen Storage Disease (example: Puri_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33741225). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the varinat as VUS (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2021

The p.R819W variant (also known as c.2455C>T), located in coding exon 16 of the GAA gene, results from a C to T substitution at nucleotide position 2455. The arginine at codon 819 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.80		Loss of methylation at R819 (P = 0.0222);Loss of methylation at R819 (P = 0.0222);
MVP		1.0
MPC		0.54
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
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: rs61736895; hg19: chr17-78091522;