17-80117015-G-A

Position:

• chr17-80117015-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4 PM3 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP’s PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all 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/CA8815664/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.45

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 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2237G>A	p.Trp746Ter	stop_gained	16/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2237G>A	p.Trp746Ter	stop_gained	16/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33

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: 0.00000399 AC: 1 AN: 250744 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135734

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461216 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726926

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

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

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Trp746Ter variant in GAA has been reported in at least 33 individuals (including 15 Italians, 5 from the UK, and 4 Chinese individuals) with Glycogen Storage Disease II (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254), and has also been reported pathogenic by GeneDx, UChicago, EGL Genetic Diagnostics, Integrated Genetics, and Invitae in ClinVar (Variation ID: 280063). This variant has been identified in 0.001% (1/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 746, 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 the homozygous state and in trans with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 26497565, 16917947). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissues, consistent with disease (PMID: 26497565, 24158270, 22237443, 21484825, 17056254, 12923862, 18285536, 16917947). Another variant at the same position with the same amino acid change, c.2238G>A (p.Trp746Ter), has been reported as a pathogenic and likely pathogenic variant in association with Glycogen Storage Disease II in ClinVar (Variation ID: 370904). 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 the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change creates a premature translational stop signal (p.Trp746*) 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 (rs752921215, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 10206684, 24158270, 25488666). ClinVar contains an entry for this variant (Variation ID: 280063). 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	Aug 13, 2018	Variant summary: GAA c.2237G>A (p.Trp746X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2560C>T, p.Arg854*). The variant allele was found at a frequency of 8.1e-06 in 245810 control chromosomes (gnomAD). c.2237G>A has been reported in the literature in multiple individuals affected with Late Onset Pompe Disease (Montalvo_2006, Liu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 05, 2020	This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP's PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2016	The W746X pathogenic variant in the GAA gene has been previously reported multiple times in association with both infantile-onset and late-onset GSDII (Beesley et al., 1998; Montalvo et al., 2006; Pittis et al., 2008). Clinical variability was described amongst individuals harboring the W746X variant and GAA enzyme activity ranged from decreased to absent (Montalvo et al., 2006; Remiche et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W746X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs752921215; hg19: chr17-78090814;