rs200483245

Variant names:

• chr17-80117047-C-T
• rs200483245
• NM_000152.5:c.2269C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.2269C>T (p.Gln757Ter), which results in a premature termination codon, is expected to undergo nonsense medicated decay resulting in absence of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient meeting the ClinGen LSD VCEP’s specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic. Additional cases have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 17723315, 29149851). There is a ClinVar entry for this variant (Variation ID: 429727, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GSD Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA294856548/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 3.74
• Publications: 4 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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 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.
• 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.2269C>T	p.Gln757*	stop_gained	Exon 16 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2269C>T	p.Gln757*	stop_gained	Exon 17 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2269C>T	p.Gln757*	stop_gained	Exon 16 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.2269C>T	p.Gln757*	stop_gained	Exon 16 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2269C>T	p.Gln757*	stop_gained	Exon 17 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2284C>T	p.Gln762*	stop_gained	Exon 16 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250796 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461274 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

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

American (AMR) AF: 0.00 AC: 0 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: 52824

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Glycogen storage disease, type II (7)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		3.7
Vest4		0.95
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	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: rs200483245; hg19: chr17-78090846;