rs386834235

Variant names:

• chr17-80105110-CT-C
• rs386834235
• NM_000152.5:c.525delT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.525delT (p.Glu176ArgfsTer45), is one of the most common variants reported in individuals with Pompe disease; over 70 patients are listed in the Erasmus database (http://www.pompevariantdatabase.nl/). It is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of c.525delT in individuals with no GAA cross-reactive immunological material in cultured skin fibroblasts i.e. CRIM-negative (PMID 22252923, 31342611), no detectable increase in GAA activity or GAA protein when cDNA with the variant was expressed in COS cells (PMID 7881422), and low expression of all GAA exons based on qRT-PCR data from a homozygous patient (PMID 25243733). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000188 in the European non-Finnish population, meeting PM2. Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, c.2481+110_2646+39del (exon 18 deletion), c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 (PM3_VeryStrong) was applied. There is a ClinVar entry for this variant (Variation ID: 4033, 2 star review status) with 8 laboratory submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Very Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220406/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:24 O:1
• Conservation: PhyloP100: -11.2
• Publications: 92 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 13 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.525delT	p.Glu176ArgfsTer45	frameshift	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.525delT	p.Glu176ArgfsTer45	frameshift	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.525delT	p.Glu176ArgfsTer45	frameshift	Exon 2 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.525delT	p.Glu176ArgfsTer45	frameshift	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.525delT	p.Glu176ArgfsTer45	frameshift	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.525delT	p.Glu176ArgfsTer45	frameshift	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000959 AC: 23 AN: 239740 AF XY: 0.0000987

Gnomad AFR exome AF: 0.000134

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: 0.000196

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 250 AN: 1456768 Hom.: 0 Cov.: 36 AF XY: 0.000148 AC XY: 107 AN XY: 724508

African (AFR) AF: 0.0000897 AC: 3 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1110822

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74364

African (AFR) AF: 0.000121 AC: 5 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000117

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
15	-	-	Glycogen storage disease, type II (16)
7	-	-	not provided (7)
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-11
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386834235; hg19: chr17-78078909;