rs142752477

chr17-80108537-G-Achr17-80108537-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000152.5(GAA):c.1124G>A(p.Arg375His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,612,868 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 7.56

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80108536-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 290225.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 17-80108537-G-A is Pathogenic according to our data. Variant chr17-80108537-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572725.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1124G>A	p.Arg375His	missense_variant	7/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1124G>A	p.Arg375His	missense_variant	7/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000322 AC: 8 AN: 248456 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134870

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460558 Hom.: 0 Cov.: 39 AF XY: 0.0000193 AC XY: 14 AN XY: 726574

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74470

Gnomad4 AFR AF: 0.000217

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000648 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 375 of the GAA protein (p.Arg375His). This variant is present in population databases (rs142752477, gnomAD 0.02%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 21757382; Invitae). 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: 572725). 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.Arg375 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18429042, 22990675, 24158270, 29422078). 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, criteria provided, single submitter	clinical testing	Baylor Genetics	May 25, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg375His variant in GAA has been reported in two Asian individuals with glycogen storage disease II (PMID: 21757382, 21484825), and has been reported in 0.02% of African chromosomes, 0.01% (3/30544) of South Asian chromosomes, and 0.0008% (1/127354) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142752477). 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 in ClinVar as a VUS by Invitae (VariationID: 572725). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg375Leu, has been reported in association with the disease in the literature and ClinVar (PMID: 25103075, 18429042, 18429042; VariationID: 283230). The phenotype of a heterozygous individual is highly specific for Glycogen Storage Disease II based on GAA activity assays with fibroblast cells (PMID: 21757382). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_supporting, PM2, PP3, PP4 (Richards 2015). -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 06, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2020	PM2, PM5, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	Previously reported in association with late-onset GSDII (Bali et al., 2011; Yang et al., 2011); Enzyme activity analysis confirmed a patient harboring R375H and an additional GAA variant had less than 1% GAA enzyme activity (Bali et al., 2011); 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: 33202836, 30275481, 21484825, 21757382) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.72
MVP		1.0
MPC		0.60
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142752477; hg19: chr17-78082336; COSMIC: COSV104403528; COSMIC: COSV104403528;