rs121907943

Variant names:

• chr17-80118271-C-T
• rs121907943
• NM_000152.5:c.2560C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PM3 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Very Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340130/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:29 O:1
• Conservation: PhyloP100: -0.165
• Publications: 102 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.
• 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.2560C>T	p.Arg854*	stop_gained	Exon 18 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2560C>T	p.Arg854*	stop_gained	Exon 19 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2560C>T	p.Arg854*	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.2560C>T	p.Arg854*	stop_gained	Exon 18 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2560C>T	p.Arg854*	stop_gained	Exon 19 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2575C>T	p.Arg859*	stop_gained	Exon 18 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000175 AC: 43 AN: 246224 AF XY: 0.000128

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 89 AN: 1456186 Hom.: 0 Cov.: 35 AF XY: 0.0000456 AC XY: 33 AN XY: 723836

African (AFR) AF: 0.00201 AC: 67 AN: 33364

American (AMR) AF: 0.000181 AC: 8 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000701 AC: 6 AN: 85566

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109074

Other (OTH) AF: 0.0000499 AC: 3 AN: 60126

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74428

African (AFR) AF: 0.00197 AC: 82 AN: 41536

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000570

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
18	-	-	Glycogen storage disease, type II (19)
8	-	-	not provided (8)
1	-	-	Cardiovascular phenotype (1)
1	-	-	GAA-related disorder (1)
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.11	N
PhyloP100		-0.17
Vest4		0.87
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs121907943; hg19: chr17-78092070;