rs764622267

Positions:

• chr17-80107718-C-G
• chr17-80107718-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM3_Supporting PM5_Supporting PS3_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.854C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 285 (p.Pro285Arg). The highest population minor allele frequency in gnomAD v4.0.1 is 0.000001784 (1/ 1120816 alleles) in the European non-finish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).This variant has been detected in at least three individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and pathogenic or likely pathogenic variants (c.1655T>C/p.Leu552Pro and c.2303C>T/Pro768Leu, none of those were confirmed in trans). 0.75 points (PMID:28196920, 19862843). (PM3_Supporting). At least two probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant, both with documented deficiency of GAA activity (PMID:28196920, 19862843). One proband had juvenile-onset (after 1 year of age) (PMID:14695532). (PP4_Moderate).Expression of the variant in COS cell type resulted in 2-10% (~ 5%) of wild-type GAA activity and evidence of abnormal GAA synthesis and processing (PMID:19862843, 14695532, 19862843). The variant was described as Class C (“less severe”), indicating that this variant may impact protein function (PMID:14695532) (PS3_Supporting).The computational predictor REVEL gives a score of 0.883, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).Another missense variant (c.853C>T, p.Pro285Ser) (PMID:18425781, 21484825, 21550241; ClinVar Variation ID 281052) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting).There is a ClinVar entry for this variant (Variation ID: 526532; 2-star review status) with four submitters classifying the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Supporting, PS3_Supporting, PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA358045/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.79

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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	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	c.854C>G	p.Pro285Arg	missense_variant	4/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000511 AC: 1 AN: 195744 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 106276

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: 2 AN: 1389866 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 688728

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.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

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	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	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	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Uncertain	0.60	T
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	D
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

Other links and lift over

dbSNP: rs764622267; hg19: chr17-78081517;