rs150868652

Positions:

chr17-80108812-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000152.5(GAA):c.1310G>A(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000833 in 1,597,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.184

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a strand (size 5) in uniprot entity LYAG_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr17-80108811-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.23942053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	8/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	8/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000650

AC:

AN:

215452

Hom.:

AF XY:

0.0000768

AC XY:

AN XY:

117228

show subpopulations

Gnomad AFR exome

AF:

0.000307

Gnomad AMR exome

AF:

0.0000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000723

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000745

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

102

AN:

1444974

Hom.:

Cov.:

AF XY:

0.0000753

AC XY:

AN XY:

717604

show subpopulations

Gnomad4 AFR exome

AF:

0.000542

Gnomad4 AMR exome

AF:

0.0000236

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000561

Gnomad4 OTH exome

AF:

0.000251

GnomAD4 genome

AF:

0.000204

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.000457

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg437His variant in GAA has been reported in one individual with suspected glycogen storage disease II (PMID: 25681614) and has been identified in 0.041% (9/21742) of African chromosomes, 0.007% (8/109392) of European (non-Finnish) chromosomes, and 0.007% (2/27668) of South Asian chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150868652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier disease. This variant has also been reported in ClinVar as a VUS by Invitae (VariationID: 456374). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg437Cys, has been reported pathogenic in association with glycogen storage disease II in the literature and ClinVar (PMID: 19862843, 24190153, 21984055, 21704464, 12601120, 24169249, 22521436, 17805474, 25388776, 25526786, 23884227, 18495398; VariationID: 189082). In summary, the clinical significance of the p.Arg437His variant is uncertain. ACMG/AMP Criteria applied: PM5, PM2, BP4 (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 437 of the GAA protein (p.Arg437His). This variant is present in population databases (rs150868652, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456374). 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 not expected to disrupt GAA protein function. This variant disrupts the p.Arg437 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12601120, 17805474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	The GAA c.1310G>A; p.Arg437His variant (rs150868652), is reported in the literature in one individual suspected of Pompe disease (Turaca 2015). This variant is also reported in ClinVar (Variation ID: 456374), and is found in the general population with an overall allele frequency of 0.008% (20/246812 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1309C>T, p.Arg437Cys) have been reported in individuals with Pompe disease and are considered pathogenic (Fukuhara 2017, Park 2021). Computational analyses predict that this variant is neutral (REVEL: 0.289). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Turaca LT et al. Novel GAA mutations in patients with Pompe disease. Gene. 2015 Apr 25;561(1):124-31. PMID: 25681614. Park KS. Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population. Children (Basel). 2021 Jul 16;8(7):601. PMID: 34356580. Fukuhara Y et al. A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. Mol Genet Metab Rep. 2017 Oct 31;14:3-9. PMID: 29124014. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 02, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 08, 2024

BP4, PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Benign

6.2

DANN

Benign

0.86

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.78

.;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

3.2

N;N

REVEL

Benign

0.29

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.29

MVP

0.94

MPC

0.14

ClinPred

0.0044

GERP RS

2.5

Varity_R

0.22

gMVP

0.71

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

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