17-80112716-G-T

Variant names:

• chr17-80112716-G-T
• rs528282884
• NM_000152.5:c.1888+5G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1888+5G>T variant alters the donor splice site consensus sequence of intron 13 in GAA. GAA activity is available for 3 patients with this variant (PMID:33202836; clinical diagnostic laboratories). Although all of these patients have been reported to have reduced GAA activity, they are all heterozygous for the c.2065G>A (p.Glu689Lys) pseudodeficiency variant. These patients were either identified as "suspected" late onset Pompe disease by newborn screen (PMID:33202836, clinical laboratory), or no further clinical information is available (clinical laboratories). Without confirmation that the variant has been found in a patient with characteristics of Pompe disease, other than reduced GAA activity that could be attributed to pseudodeficiency, PP4 is not met at the current time. All 3 patients with documented GAA deficiency are compound heterozygous for the variant along with c.2065G>A (p.Glu689Lys), and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.-32-13T>G (ClinVar Variation ID: 4027) (with c.510C>T, which is believed to be a modifier, typically occurring in cis with c.-32-13T>G), c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) (PMID:33202836, clinical laboratory), and c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1). However, because PP4 was not met, and it is unclear if these patients have Pompe disease, PM3 is not met at any weight at the current time. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006 (2/33202 alleles) in the Latino population and, in gnomAD v4.1, the highest population MAF is 0.0004094 (24/58624 alleles) in the Admixed American population both of which are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, results from RNA studies on this variant are not available. SpliceAI indicates that the variant has no significant impact on splicing (donor loss score= 0.04; acceptor gain 126 bp downstream, score 0.11=, donor gain 83 bp downstream, score=0.13) (BP4). There is a ClinVar entry for this variant (Variation ID: 283971). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM2_Supporting, BP4(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815512/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Uncertain significance reviewed by expert panel U:9
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1888+5G>T		splice_region_variant, intron_variant	Intron 13 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1888+5G>T		splice_region_variant, intron_variant	Intron 13 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.00

GnomAD3 exomes AF: 0.0000134 AC: 3 AN: 224656 Hom.: 0 AF XY: 0.00000812 AC XY: 1 AN XY: 123172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000618

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: 0.000179

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1452246 Hom.: 0 Cov.: 33 AF XY: 0.00000831 AC XY: 6 AN XY: 721816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000693

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: 9.02e-7

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.000317

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:4

May 21, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1888+5G>T variant alters the donor splice site consensus sequence of intron 13 in GAA. GAA activity is available for 3 patients with this variant (PMID: 33202836; clinical diagnostic laboratories). Although all of these patients have been reported to have reduced GAA activity, they are all heterozygous for the c.2065G>A (p.Glu689Lys) pseudodeficiency variant. These patients were either identified as "suspected" late onset Pompe disease by newborn screen (PMID: 33202836, clinical laboratory), or no further clinical information is available (clinical laboratories). Without confirmation that the variant has been found in a patient with characteristics of Pompe disease, other than reduced GAA activity that could be attributed to pseudodeficiency, PP4 is not met at the current time. All 3 patients with documented GAA deficiency are compound heterozygous for the variant along with c.2065G>A (p.Glu689Lys), and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.-32-13T>G (ClinVar Variation ID: 4027) (with c.510C>T, which is believed to be a modifier, typically occurring in cis with c.-32-13T>G), c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) (PMID: 33202836, clinical laboratory), and c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1). However, because PP4 was not met, and it is unclear if these patients have Pompe disease, PM3 is not met at any weight at the current time. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006 (2/33202 alleles) in the Latino population and, in gnomAD v4.1, the highest population MAF is 0.0004094 (24/58624 alleles) in the Admixed American population both of which are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, results from RNA studies on this variant are not available. SpliceAI indicates that the variant has no significant impact on splicing (donor loss score= 0.04; acceptor gain 126 bp downstream, score 0.11=, donor gain 83 bp downstream, score=0.13) (BP4). There is a ClinVar entry for this variant (Variation ID: 283971). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM2_Supporting, BP4 (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024). -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 13 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 (rs528282884, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of Pompe disease (PMID: 33202836; internal data). ClinVar contains an entry for this variant (Variation ID: 283971). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 21, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:3

Nov 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second GAA variant in patients with suspected late onset Pompe disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ficicioglu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 33202836) -

not specified Uncertain:1

Sep 23, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1888+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. Two also predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224656 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1888+5G>T has been reported in the literature in two individuals suspected of late onset Glycogen Storage Disease, Type 2 (Pompe Disease), both who harbored pathogenic variants and c.2065G>A, reported as a pseudodeficiency allele (Ficicioglu_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33202836). ClinVar contains an entry for this variant (Variation ID: 283971). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GAA-related disorder Uncertain:1

Mar 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GAA c.1888+5G>T variant is predicted to interfere with splicing. This variant was reported in an individual with late onset glycogen storage disease; however, pathogenicity was not established (Ficicioglu et al. 2020. PubMed ID: 33202836). This variant is reported in 0.0060% of alleles in individuals of Latino descent in gnomAD. An expert ClinGen panel has interpreted this variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/283971). Splicing prediction programs do not predict a splicing impact for this variant (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.040		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: rs528282884; hg19: chr17-78086515;