17-80107574-C-T

Position:

chr17-80107574-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_SupportingPM3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.710C>T variant in GAA is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 237 (p.Ala237Val). A patient with late onset Pompe disease and this variant has been described with a severely reduced GAA activity (<10% normal) and an increase of total glycogen in muscle (PMID:15668445, 17573812, 17643989) (PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.877G>A (p.Gly293Arg) (PMID:15668445, 17573812, 17643989) (PM3_Supporting). Another patient has been reported who is compound heterozygous for the variant and p.Met173del (PMID:28196920). However, the cDNA changes for these variants were not provided and therefore the data was not included. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00013 (4/30616 alleles) in the South Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had "greater than 2% wild-type GAA activity", but the activity was not provided (PS3 not met). The computational predictor REVEL gives a score of 0.693 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen LSD VCEP on November 2, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116619/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:7

Conservation

PhyloP100: 5.96

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.

PM2

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

PM3

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

PP4

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.710C>T	p.Ala237Val	missense_variant	4/20	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.710C>T	p.Ala237Val	missense_variant	4/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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:

0.0000199

AC:

AN:

250946

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460806

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

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

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:1Uncertain:4

Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 02, 2022	The NM_000152.5:c.710C>T variant in GAA is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 237 (p.Ala237Val). A patient with late onset Pompe disease and this variant has been described with a severely reduced GAA activity (<10% normal) and an increase of total glycogen in muscle (PMID: 15668445, 17573812, 17643989) (PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.877G>A (p.Gly293Arg) (PMID: 15668445, 17573812, 17643989) (PM3_Supporting). Another patient has been reported who is compound heterozygous for the variant and p.Met173del (PMID: 28196920). However, the cDNA changes for these variants were not provided and therefore the data was not included. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00013 (4/30616 alleles) in the South Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had "greater than 2% wild-type GAA activity", but the activity was not provided (PS3 not met). The computational predictor REVEL gives a score of 0.693 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP on November 2, 2022) -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Ala237Val variant in GAA has been reported in 1 German individual with Glycogen Storage Disease II (PMID: 15668445), and has also been reported as a VUS by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4035). This variant has been identified in 0.013% (4/30616) of South Asian chromosomes and 0.001% (1/113342) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907944). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ala237Val variant is pathogenic (PMID: 15668445). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PM2, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the GAA protein (p.Ala237Val). This variant is present in population databases (rs121907944, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 15668445). ClinVar contains an entry for this variant (Variation ID: 4035). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). This variant disrupts the p.A237G amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 31086307), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

GLYCOGEN STORAGE DISEASE II, ADULT FORM

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 25, 2005

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 05, 2022

Variant summary: GAA c.710C>T (p.Ala237Val) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of 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 2e-05 in 250946 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.710C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected by late-onset Pompe disease who has been subsequently cited by others (example, Anneser_2005, Muller-Felber_2007, Schoser_2007). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

GAA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

The GAA c.710C>T variant is predicted to result in the amino acid substitution p.Ala237Val. This variant has been reported in the compound heterozygous state with the GAA c.877G>A (p.Gly293Arg) variant in an individual with late onset Pompe disease (Anneser et al. 2005. PubMed ID: 15668445; Schoser et al. 2007. PubMed ID: 17573812; Müller-Felber et al. 2007. PubMed ID: 17643989). Functional studies have shown that this variant impacts GAA protein function (Flanagan et al. 2009. PubMed ID: 19862843). Of note, another variant impacting this same amino acid [c.710C>G (p.Ala237Gly)] has been reported in an individual with glycogen storage disease 2 (Supplemental Table S3, Kishnani et al. 2019. PubMed ID: 31086307). The c.710C>T variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD and is reported as a variant of uncertain significance by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4035/) At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17027861, 15668445, 17643989, 34426522, 19343043, 22253258, 17573812, 30275481, 19862843) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.1

.;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.8

.;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.019

.;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.99

.;D;D

Vest4

0.94

MutPred

0.83

Loss of catalytic residue at A237 (P = 0.21);Loss of catalytic residue at A237 (P = 0.21);Loss of catalytic residue at A237 (P = 0.21);

MVP

0.96

MPC

0.44

ClinPred

0.94

GERP RS

5.2

Varity_R

0.90

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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