rs766680292

Variant names:

• chr17-80110785-G-A
• rs766680292
• NM_000152.5:c.1496G>A
• GAA p.Trp499*

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP4 PM3_Supporting PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.1496G>A (p.Trp499Ter) is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross reactive immunological material in cultured skin fibroblasts from a patient with this variant (PMIDs 19775921, 22252923, and 25741864). Therefore, PVS1 can be applied. This patient, who has infantile onset Pompe disease, meets the ClinGen LSD VCEP’s specifications for PP4, and is homozygous for the variant, meeting PM3_Supporting. Additional patients have been reported, including 2 homozygous Tunisian patients (PMID 32125626), but the residual GAA activity was not provided, and this data was not included. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which meets PM2. There is a ClinVar entry for this variant (Variation ID 556959, 1 star review status), with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815357/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.39
• Publications: 6 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: G2P, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1496G>A	p.Trp499*	stop_gained	Exon 10 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1496G>A	p.Trp499*	stop_gained	Exon 11 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1496G>A	p.Trp499*	stop_gained	Exon 10 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1496G>A	p.Trp499*	stop_gained	Exon 10 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1496G>A	p.Trp499*	stop_gained	Exon 11 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1511G>A	p.Trp504*	stop_gained	Exon 10 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251198 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Glycogen storage disease, type II (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766680292;

hg19: chr17-78084584;