rs786204467

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_SupportingPM3_StrongPVS1_StrongPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1A>G (p.Met1Val, aka p.Met1?) start loss variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong; PMIDs 22644586, 30192042, 22252923). This variant is absent in gnomAD v2.1.1. (PM2_Supporting).This variant has been detected in at least 5 individuals with Pompe disease. Three individuals are compound heterozygous for the variant and another pathogenic or likely pathogenic variant in GAA, including c.2608T>C (pArg870Ter) (pathogenic based on classification by the ClinGen LD VCEP, confirmed in trans, 1 point, PMID:33301762), exon 6-10 deletion (pathogenic, phase confirmed, 1 point, PMID:37542277), and c.1831G>A (p.Gly611Ser), LP based on classification by the ClinGen LD VCEP; phase unconfirmed, 0.25 points, PMID:33250842). One individual was homozygous for the variant (0.5 point, 29422078). Another patient is compound heterozygous for the variant and another variant in GAA, either c.1714C>G (p.His572Asp) (PMID:33301762). The allelic data from this patient will be used in the assessment of the second variant and is not included here to avoid circular logic. Total 2.75 points (PM3_Strong). At least two patients with this variant had documented GAA deficiency with <10% of the normal mean control level of GAA activity in dried blood spots (PMID:33301762, 37542277). One homozygous patient had documented symptoms of severe infantile onset of the disease and was reported to be on enzyme replacement therapy for Pompe disease, and CRIM negative (PMID:29422078) (PP4_Moderate).Three different missense variants (c.2T>C, c.1A>T, c.3G>A) (ClinVar Variation IDs: 984802, 984798, 972816, respectively], in the same codon have been classified as Pathogenic/Likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP.In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA273952/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GAA
NM_000152.5 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 1.38

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 Pathogenic. Variant got 11 ACMG points.

PVS1

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

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.1A>G	p.Met1?	start_lost	2/20	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.1A>G	p.Met1?	start_lost	2/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457632

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724840

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 05, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys103 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1109266, 14695532, 18429042, 18607768, 24158270, 29181627). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188785). Disruption of the initiator codon has been observed in individuals with Pompe disease (PMID: 22252923, 29124014, 29422078). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 22, 2023	The homozygous start loss variant c.1A>G (p.Met1?) has been identified in a proband with muscle weakness and hypotonia, . This variant has not been found in gnomAD (aggregated) database. This has been previously reported PMID: 18429042 This homozygous variant start loss variant c.1A>G (p.Met1?) has been identified in 6 more patient and in 4 patient in heterozygous state. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 15, 2014	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 08, 2024	The NM_000152.5:c.1A>G (p.Met1Val, aka p.Met1?) start loss variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong; PMIDs 22644586, 30192042, 22252923). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). This variant has been detected in at least 5 individuals with Pompe disease. Three individuals are compound heterozygous for the variant and another pathogenic or likely pathogenic variant in GAA, including c.2608T>C (pArg870Ter) (pathogenic based on classification by the ClinGen LD VCEP, confirmed in trans, 1 point, PMID: 33301762), exon 6-10 deletion (pathogenic, phase confirmed, 1 point, PMID: 37542277), and c.1831G>A (p.Gly611Ser), LP based on classification by the ClinGen LD VCEP; phase unconfirmed, 0.25 points, PMID:33250842). One individual was homozygous for the variant (0.5 point, 29422078). Another patient is compound heterozygous for the variant and another variant in GAA, either c.1714C>G (p.His572Asp) (PMID: 33301762). The allelic data from this patient will be used in the assessment of the second variant and is not included here to avoid circular logic. Total 2.75 points (PM3_Strong). At least two patients with this variant had documented GAA deficiency with <10% of the normal mean control level of GAA activity in dried blood spots (PMID: 33301762, 37542277). One homozygous patient had documented symptoms of severe infantile onset of the disease and was reported to be on enzyme replacement therapy for Pompe disease, and CRIM negative (PMID: 29422078) (PP4_Moderate). Three different missense variants (c.2T>C, c.1A>T, c.3G>A) (ClinVar Variation IDs: 984802, 984798, 972816, respectively], in the same codon have been classified as Pathogenic/Likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 8, 2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.014

T;.;T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.90

D;D;.;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

-0.26

PROVEAN

Benign

-0.34

.;.;N;N

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.0050

.;.;B;B

Vest4

0.85

MutPred

1.0

Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);Gain of methylation at R4 (P = 0.2438);

MVP

0.92

ClinPred

0.96

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.79

gMVP

0.61

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

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