Variant chr17-80107718-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000152.5(GAA):c.854C>G(p.Pro285Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,389,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.79

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-80107718-C-G is Pathogenic according to our data. Variant chr17-80107718-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107718-C-G is described in Lovd as [Pathogenic]. Variant chr17-80107718-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.854C>G	p.Pro285Arg	missense_variant	4/20	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.854C>G	p.Pro285Arg	missense_variant	4/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000511

AC:

AN:

195744

Hom.:

AF XY:

0.00

AC XY:

AN XY:

106276

show subpopulations

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:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1389866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688728

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000188

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro285 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21484825, 21550241). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. ClinVar contains an entry for this variant (Variation ID: 225114). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 28196920). This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 285 of the GAA protein (p.Pro285Arg). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Pro285Arg variant in GAA has been reported in at least 3 individuals (including 1 German individual) with Glycogen Storage Disease II (PMID: 14695532, 12213618, 28196920; DOI: 10.1016/S1472-6483(16)30370-4), and has also been reported pathogenic by Ambry Genetics and as a VUS by Invitae in ClinVar (Variation ID: 225114). This variant has been identified in 0.001% (1/87084) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764622267). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Pro285Arg variant may impact GAA activity (PMID: 14695532, 19862843, 12213618). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Pro285Arg variant is pathogenic (PMID: 14695532, 12213618). One pathogenic variant at the same position, p.Pro285Ser, has been reported in association with Glycogen Storage Disease II (Variation ID: 281052). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity in their leukocytes or fibroblasts and no known pseudodeficiency alleles in at least one individual (PMID: 28196920, 12213618). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant, individuals with phenotypes highly specific for Glycogen Storage Disease II, and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PP4_Moderate, PM3_Supporting, PM2, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 10, 2023

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2014

The c.854C>G (p.P285R) alteration is located in exon 4 (coding exon 3) of the GAA gene. The alteration results from a C to G substitution at nucleotide position 854, causing the Proline (P) at amino acid position 285 to be replaced by an Arginine (R). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the GAA c.854C>G alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The amino acid change has been observed in affected individuals: _x000D_ This missense change has been reported in a German patient with late infantile/juvenile onset GSDII (Bodamer, 2002). The patient had this mild P285R mutation in combination with a severe mutation on the other allele. This alteration has also been reported homozygous in an Iranian boy presenting at age 2 with Pompe disease (Nazari, 2017). The altered amino acid is conserved throughout evolution:_x000D_ The p.P285 amino acid position is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.P285R amino acid is located in the N-terminal domain of the GAA protein (Flanagan, 2009). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis demonstrated that the p.P285R alteration resulted in 7-10% residual enzyme activity in vitro (Bodamer, 2002). A subsequent study confirmed partial loss of enzyme activity for glycogen and an artificial substrate classified it as a mild mutation (Hermans, 2004). Flanagan et al. (2009) also determined that the pharmacological chaperone 1-Deoxynojirimycin (DNJ) was able to increase the GAA enzyme activity in fibroblast cells expressing this mutant and may be a potential therapeutic treatment for GSDII patients. The alteration is predicted deleterious by in silico models:_x000D_ The p.P285R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

4.2

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.79

Gain of MoRF binding (P = 0.0049);Gain of MoRF binding (P = 0.0049);

MVP

1.0

MPC

0.56

ClinPred

1.0

GERP RS

5.1

Varity_R

0.94

gMVP

0.90

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

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

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