rs786204467

Variant names:

• chr17-80104587-A-G
• rs786204467
• NM_000152.5:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80104587-A-G
• chr17-80104587-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PM3_Strong PVS1_Strong PP4_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
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.38
• Publications: 26 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: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1A>G	p.Met1?	start_lost	Exon 2 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1A>G	p.Met1?	start_lost	Exon 2 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32

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: 1 AN: 1457632 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724840

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110522

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

May 15, 2014

Counsyl

Significance: Likely pathogenic

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 22, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 08, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Sep 08, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Pompe disease (PMID: 22252923, 29124014, 29422078). ClinVar contains an entry for this variant (Variation ID: 188785). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	13
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	N
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.26	T
PhyloP100		1.4
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	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.79
gMVP		0.61
Mutation Taster		=5/195	disease causing (ClinVar)

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: rs786204467; hg19: chr17-78078386;