17-80118319-C-T

Variant names:

• chr17-80118319-C-T
• rs780321415
• NM_000152.5:c.2608C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: This variant, c.2608C>T (p.Arg870Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting the ClinGen LSD VCEP’s threshold for PM2. This variant has been reported in patients meeting the ClinGen LSD VCEP’s PP4 criterion who also carry a known pathogenic variant in GAA, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). There is a ClinVar entry for this variant (Variation ID: 189009, 2 star review status) with five submitters 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. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274250/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 0.218
• Publications: 25 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.2608C>T	p.Arg870*	stop_gained	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2608C>T	p.Arg870*	stop_gained	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2608C>T	p.Arg870*	stop_gained	Exon 18 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.2608C>T	p.Arg870*	stop_gained	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2608C>T	p.Arg870*	stop_gained	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2623C>T	p.Arg875*	stop_gained	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152042 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000266 AC: 6 AN: 225354 AF XY: 0.0000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000343 AC: 49 AN: 1429602 Hom.: 0 Cov.: 35 AF XY: 0.0000311 AC XY: 22 AN XY: 707142

African (AFR) AF: 0.00 AC: 0 AN: 32776

American (AMR) AF: 0.0000239 AC: 1 AN: 41830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.0000411 AC: 45 AN: 1093896

Other (OTH) AF: 0.0000340 AC: 2 AN: 58844

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Glycogen storage disease, type II (11)
6	-	-	not provided (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	0.97
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.10	N
PhyloP100		0.22
Vest4		0.92
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=3/197	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: rs780321415; hg19: chr17-78092118; COSMIC: COSV100163435; COSMIC: COSV100163435;