NM_000152.5:c.265C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID:28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 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 Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3.(Classification approved by the ClinGen LSD VCEP on December 20, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814832/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:8

Conservation

PhyloP100: 2.44

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

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 link	c.265C>T	p.Arg89Cys	missense_variant	Exon 2 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.265C>T	p.Arg89Cys	missense_variant	Exon 2 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152246

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:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000250

AC:

AN:

248200

Hom.:

AF XY:

0.000334

AC XY:

AN XY:

134800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1460632

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74500

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:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:1Uncertain:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the GAA protein (p.Arg89Cys). This variant is present in population databases (rs534192892, gnomAD 0.2%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (internal data). ClinVar contains an entry for this variant (Variation ID: 456412). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg89 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25626711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Jan 02, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID: 28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 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 Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. (Classification approved by the ClinGen LSD VCEP on December 20, 2022) -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:2

Nov 15, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.265C>T (p.Arg89Cys) results in a non-conservative amino acid change located in the P-type trefoil domain 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 0.00025 in 248200 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00025 vs 0.0042), allowing no conclusion about variant significance. c.265C>T has been reported in the literature in individuals affected with a positive newborn screening result for GAA-related disease (example: Sniderman_2023, Tang_2020, Internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37087815, 33073007, 33560568, No_PMID). ClinVar contains an entry for this variant (Variation ID: 456412). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:2

Dec 04, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.0011

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;D;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

4.3

.;.;H;H

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.5

.;.;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;D;D

Vest4

0.85, 0.85

MutPred

0.91

Loss of phosphorylation at S88 (P = 0.0837);Loss of phosphorylation at S88 (P = 0.0837);Loss of phosphorylation at S88 (P = 0.0837);Loss of phosphorylation at S88 (P = 0.0837);

MVP

0.97

MPC

0.63

ClinPred

0.81

GERP RS

4.0

Varity_R

0.91

gMVP

0.89

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