rs376067362

Positions:

chr17-80110793-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID:24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompedisease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815358/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:12

Conservation

PhyloP100: 4.28

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 2 ACMG points.

PM2

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

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1504A>G	p.Met502Val	missense_variant	10/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.1504A>G	p.Met502Val	missense_variant	10/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

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:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251226

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000103

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

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:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:1Uncertain:8

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the GAA protein (p.Met502Val). This variant is present in population databases (rs376067362, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 24158270, 33202836; 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: 439746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Illumina Laboratory Services, Illumina	Dec 07, 2018	The GAA c.1504A>G (p.Met502Val) missense variant has been reported in one study and found in one individual with late-onset glycogen storage disease II in a compound heterozygous state with a known pathogenic allele (Remiche et al. 2014). The p.Met502Val variant was absent from 100 ethnically matched healthy controls but is reported at a frequency of 0.000121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Although functional studies were not available, Remiche et al. (2014) reported muscle GAA enzyme residual activity in the affected individual to be 14% of normal. Based on the limited evidence, the p.Met502Val variant is classified as a variant of unknown significance, but suspicious for pathogenicity for glycogen storage disease, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 01, 2023	The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID: 24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 01, 2022	- -
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 heterozygous p.Met502Val variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 24158270). This variant has been identified in 0.010% (13/128968) of European (non-Finnish) chromosomes and 0.003% (1/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376067362). 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 as a VUS by Invitae, EGL Genetic Diagnostics, Illumina, and ARUP Laboratories in ClinVar (Variation ID: 439746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Methionine (Met) at position 502 is not highly conserved in mammals and evolutionary distant species, and one species (American alligator) carries a Valine (Val), raising the possibility that this change at this position may be tolerated. This variant was reported in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II (PMID: 24158270). In summary, the clinical significance of the p.Met502Val variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33202836, 30985853, 24158270) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.75

D;D

Eigen

Benign

-0.021

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

.;T

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.035

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

0.80

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.51

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.16

B;B

Vest4

0.31

MVP

0.95

MPC

0.20

ClinPred

0.11

GERP RS

5.4

Varity_R

0.77

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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