rs778032599

Positions:

chr17-80118809-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2799+4A>G is located in the donor splice site region of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.62 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). Two individuals with Pompe disease have been reported to have this variant; one has documentation of deficient GAA activity and is on enzyme replacement therapy (PMID:26873529) (PP4_Moderate), and the second patient has limb girdle muscular dystrophy (PMID:30564623). Both individuals are compound heterozygous for this variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.1548G>A (p.Trp516Ter) (PMID:26873529) or c.2501_2502delCA (PMID:30564623); the phase is unknown in each case (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16172 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additional variants in this splice region have been identified, including c.2799+2C>T, c.2799+2C>A, and c.2799+5G>A (PMID:28265479); all currently classified by the ClinGen LD VCEP as variants of uncertain significance. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815855/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GAA
NM_000152.5 splice_donor_region, intron

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:5

Conservation

PhyloP100: 1.79

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

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 linkuse as main transcript	c.2799+4A>G		splice_donor_region_variant, intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2799+4A>G		splice_donor_region_variant, intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00000400

AC:

AN:

249970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.0000618

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460630

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000227

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change falls in intron 19 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778032599, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of GAA-related conditions (PMID: 26873529, 30564623; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 286228). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 27, 2023	The NM_000152.5:c.2799+4A>G is located in the donor splice site region of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.62 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). Two individuals with Pompe disease have been reported to have this variant; one has documentation of deficient GAA activity and is on enzyme replacement therapy (PMID: 26873529) (PP4_Moderate), and the second patient has limb girdle muscular dystrophy (PMID: 30564623). Both individuals are compound heterozygous for this variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.1548G>A (p.Trp516Ter) (PMID: 26873529) or c.2501_2502delCA (PMID: 30564623); the phase is unknown in each case (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16172 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additional variants in this splice region have been identified, including c.2799+2C>T, c.2799+2C>A, and c.2799+5G>A (PMID: 28265479); all currently classified by the ClinGen LD VCEP as variants of uncertain significance. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023) -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 18, 2024

Variant summary: GAA c.2799+4A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249970 control chromosomes. c.2799+4A>G has been reported in the literature in an individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease) confirmed by reduced GAA activity in leukocytes and a second individual with Limb-Girdle Muscular Dystrophy (examples: Stepien_2016, Nallamilli_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564623, 26873529). ClinVar contains an entry for this variant (Variation ID: 286228). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.62

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over