rs1042395

Variant names:

• chr17-80105870-G-A
• rs1042395
• NM_000152.5:c.668G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80105870-G-A
• chr17-80105870-G-C
• chr17-80105870-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145791/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.66 (33595 hom., cov: 33)
  • Exomes 𝑓: 0.71 (369171 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: -0.0360
• Publications: 61 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.668G>A	p.Arg223His	missense_variant	Exon 3 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.668G>A	p.Arg223His	missense_variant	Exon 3 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99833 AN: 151982 Hom.: 33582 Cov.: 33

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.666 AC: 162329 AN: 243594 AF XY: 0.681

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.711 AC: 1030164 AN: 1448490 Hom.: 369171 Cov.: 58 AF XY: 0.712 AC XY: 512807 AN XY: 720028

African (AFR) AF: 0.539 AC: 17981 AN: 33368

American (AMR) AF: 0.489 AC: 21802 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20386 AN: 26068

East Asian (EAS) AF: 0.559 AC: 22109 AN: 39564

South Asian (SAS) AF: 0.670 AC: 57680 AN: 86142

European-Finnish (FIN) AF: 0.760 AC: 34338 AN: 45174

Middle Eastern (MID) AF: 0.794 AC: 4121 AN: 5188

European-Non Finnish (NFE) AF: 0.730 AC: 809122 AN: 1108302

Other (OTH) AF: 0.709 AC: 42625 AN: 60102

GnomAD4 genome AF: 0.657 AC: 99875 AN: 152100 Hom.: 33595 Cov.: 33 AF XY: 0.654 AC XY: 48653 AN XY: 74362

African (AFR) AF: 0.536 AC: 22228 AN: 41480

American (AMR) AF: 0.558 AC: 8525 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2671 AN: 3468

East Asian (EAS) AF: 0.539 AC: 2787 AN: 5174

South Asian (SAS) AF: 0.657 AC: 3162 AN: 4814

European-Finnish (FIN) AF: 0.775 AC: 8213 AN: 10594

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50039 AN: 67972

Other (OTH) AF: 0.667 AC: 1409 AN: 2112

Alfa AF: 0.694 Hom.: 88041

Bravo AF: 0.637

TwinsUK AF: 0.723 AC: 2681

ALSPAC AF: 0.724 AC: 2792

ESP6500AA AF: 0.544 AC: 2396

ESP6500EA AF: 0.738 AC: 6348

ExAC AF: 0.675 AC: 81893

Asia WGS AF: 0.580 AC: 2021 AN: 3476

EpiCase AF: 0.742

EpiControl AF: 0.742

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Benign:7

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2015

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.927% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Uncertain	0.46	T;D;D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T;.;T
MetaRNN	Benign	0.000017	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.3	.;M;M
PhyloP100		-0.036
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.54	.;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.21	.;B;B
Vest4		0.050, 0.049
MPC		0.14
ClinPred		0.033	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.69
Mutation Taster		=55/45	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042395; hg19: chr17-78079669; COSMIC: COSV56406846; COSMIC: COSV56406846;