17-80107802-C-T

Variant names:

• chr17-80107802-C-T
• rs778580823
• NM_000152.5:c.861C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000152.5(GAA):​c.861C>T​(p.Pro287Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000794 in 1,611,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P287P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: -4.49
• Publications: 5 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-80107802-C-T is Benign according to our data. Variant chr17-80107802-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284775.
• BP7: Synonymous conserved (PhyloP=-4.49 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 5 of 20	NP_000143.2
	GAA	NM_001079803.3		c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 6 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 5 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 5 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 6 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.861C>T	p.Pro287Pro	splice_region synonymous	Exon 5 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000901 AC: 22 AN: 244104 AF XY: 0.0000827

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000822 AC: 120 AN: 1459146 Hom.: 0 Cov.: 56 AF XY: 0.0000923 AC XY: 67 AN XY: 725866

African (AFR) AF: 0.000239 AC: 8 AN: 33458

American (AMR) AF: 0.0000449 AC: 2 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86106

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.0000738 AC: 82 AN: 1111386

Other (OTH) AF: 0.0000830 AC: 5 AN: 60242

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type II Uncertain:4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 06, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous c.861C>T (p.Pro287=) variant in GAA has been reported in at least one individual with Glycogen Storage Disease II and has been identified in 0.020% (2/10132) of Ashkenazi Jewish chromosomes, 0.016% (5/30388) of South Asian chromosomes, and 0.01% (13/124796) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778580823). 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 a VUS by EGL Genetic Diagnostics and likely benign by Invitae in ClinVar (Variation ID: 284775). This variant is located in the first base of the exon, which is part of the 3' splice region. In vitro functional studies provide some evidence that the c.861C>T variant may impact GAA splicing and protein levels (PMID: 27189384, 23000108). However, these types of assays may not accurately represent biological function. Computational splice prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been reported in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II, slightly increasing the likelihood that the c.861C>T variant is pathogenic (PMID: 27189384). However, this variant has also been reported in an individual reported to have two additional reported pathogenic variants (PMID: 22644586). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, BP7, BP4, PM3_Supporting, PS3_Supporting, PP4 (Richards 2015).

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2

Apr 15, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 284775; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27189384, 22644586, 23000108)

Dec 08, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jan 07, 2019

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.861C>T (p.Pro287Pro) 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. 5/5 computational 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 8.5e-05 in 270968 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (8.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.861C>T has been reported in the literature in at least one individual with low GAA activity but without symptoms (van Capelle_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Wens_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as ikely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiovascular phenotype Benign:1

May 28, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.41
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778580823; hg19: chr17-78081601;