17-80104704-C-T

Position:

• chr17-80104704-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM3_Supporting PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the South Asian population, meeting PM2. The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975), meeting PM3_Supporting. In addition, a large family has been reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Additional cases with this variant have been reported but were not included because residual enzyme activity was not provided and therefore PP4 could not be assessed. There is a ClinVar entry for this variant (Variation ID: 426593, 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 Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814791/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.118C>T	p.Arg40*	stop_gained	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.118C>T	p.Arg40*	stop_gained	2/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248728 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135040

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460770 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 06, 2020	This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the South Asian population, meeting PM2. The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975), meeting PM3_Supporting. In addition, a large family has been reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Additional cases with this variant have been reported but were not included because residual enzyme activity was not provided and therefore PP4 could not be assessed. There is a ClinVar entry for this variant (Variation ID: 426593, 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 Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Arg40*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs767409395, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 24107549, 29124014). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426593). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2016	Variant summary: The c.118C>T variant in GAA is a nonsense mutation. The mutation is predicted to lead to a truncated/absent protein. It has been reported in multiple affected individuals with Pompe disease, including homozygous pt with classic infantile onset and nearly absent residual enzyme activity. The variant is present in ExAC at low frequency (0.0009%) which does not exceed the maximum frequency for a pathogenic variant in GAA gene (0.42%). Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 18, 2019	The p.Arg40Ter variant in GAA has been reported in at least 12 individuals (7 Italian, 1 German, 1 French, 1 Portuguese, and 1 Pakistani individuals) with Glycogen Storage Disease II, segregated with disease in 7 affected relatives from 1 family (PMID: 17723315, 9266392, 22676651, 11071489, 20559845, 24107549), and has been identified in 0.001% (4/275242) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767409395). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic in ClinVar by GeneDx and Integrated Genetics/Laboratory Corporation of America (Variation ID: 426593). This nonsense variant leads to a premature termination codon at position 40, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in the homozygous state in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg40Ter variant is pathogenic (PMID: 17723315, 22958975, 22676651). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low relative GAA activity consistent with disease (PMID: 22676651, 22958975, 24107549, 17723315). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PP4, PM2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	Apr 22, 2022	The c.118C>T (p.Arg40Ter) in compound heterocigosity with c.-32-13T>G GAA variant has been reported in our laboratory in a 52-year-old woman from England with diagnosis of Pompe disease (onset 10 years before) with parents and four asymptomatic children and alpha-1,4-glucosidase lysosomal enzyme activity study: 0.4 µmol/L/h (cut-off value: >2.0). Pompe Variant Database describes this phenotype in eight patients, all diagnosed between the ages of 20 and 60. It has been previously reported in patients with Pompe disease both in the homozygous and heterozygous state (PMID: 17723315, 24107549, 7603530, 29124014, 9266392, 22676651, 11071489, 20559845, 22958975). This variant is present in population databases (gnomAD allele frequency 0.00001428). ClinVar contains an entry for this variant (Variation ID: 426593) reviewed by expert panel. Functional studies in transfected COS cells and patient fibroblast cells showed that R40X resulted in reduced enzyme activity and impacts the function of the protein (PMID: 24150945). In summary, c.118C>T (p.Arg40Ter) GAA variant meets our criteria to be classified as pathogenic for Pompe disease in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 30, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2018	The R40X pathogenic variant in the GAA gene has been reported previously in multiple individuals with glycogen storage disease type II in the homozygous state, as well as in the heterozygous state in the presence of a second GAA variant (McCready et al., 2007; Sampaolo et al., 2013; Reuser et al., 1995). Additionally, functional studies in transfected COS cells and patient fibroblast cells showed that R40X resulted in reduced enzyme activity and impacts the function of the protein (Reuser et al., 1995). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R40X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.083	N
Vest4		0.63
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs767409395; hg19: chr17-78078503;