rs886042086

Variant names:

• chr17-80107717-C-T
• rs886042086
• NM_000152.5:c.853C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM2_Supporting PM3 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.853C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 285 (p.Pro285Ser). The highest population minor allele frequency in gnomAD is 0.00009 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. REVEL (in silico meta predictor for missense changes) score = 0.757 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion. At least two patients had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PP4_Moderate). Two individuals with Pompe disease have been reported who are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.2237G>A (p.Trp746Ter)(PMID:21484825)(0.5 points) or c.1354_1372del19 (PMID:21550241)(0.5 points), Total 1 point (PM3). This variant results in <5% GAA activity when expressed in COS cells, and was classified as Class C ("less severe") by Kroos et al, 2012 (PMID:22644586), meeting the ClinGen LSD VCEP criteria for PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 281052, 1 star review status) with 5 submitters, two classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PP3, PM2_supporting, PM3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603793/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.000074 (0 hom., cov: 34)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 7.79
• Publications: 9 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_pathogenic. The variant received 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.
• 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 rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.853C>T	p.Pro285Ser	missense_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.853C>T	p.Pro285Ser	missense_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 10 AN: 135790 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000269

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202738 AF XY: 0.00000906

Gnomad AFR exome AF: 0.0000679

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000736 AC: 10 AN: 135790 Hom.: 0 Cov.: 34 AF XY: 0.0000457 AC XY: 3 AN XY: 65688

African (AFR) AF: 0.000269 AC: 10 AN: 37132

American (AMR) AF: 0.00 AC: 0 AN: 13598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3202

East Asian (EAS) AF: 0.00 AC: 0 AN: 4722

South Asian (SAS) AF: 0.00 AC: 0 AN: 4088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61504

Other (OTH) AF: 0.00 AC: 0 AN: 1782

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7 Uncertain:1

Jan 22, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Pro285Ser variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 21550241, 21484825, 30564623), and has also been reported as a pathogenic variant by EGL Genetic Diagnostics and Integrated Genetics and a VUS by Counsyl in ClinVar (Variation ID: 281052). This variant has been identified in 0.013% (3/22640) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886042086). 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.Pro285Ser variant may impact GAA activity and slightly reduce GAA levels (PMID: 22644586). 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.Pro285Ser variant is pathogenic (PMID: 21550241, 21484825). One additional pathogenic variant at the the same position, p.Pro285Arg, was reported in association with disease, supporting that a change at this position may not be tolerated (Variation ID: 225114). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21550241, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on evidence from in vitro functional studies, low frequency in the general population, and another pathogenic variant reported at the same position. ACMG/AMP Criteria applied: PS3, PM5, PM2, PM3_Supporting, PP3, PP4 (Richards 2015). -

Dec 13, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.853C>T (p.Pro285Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 27092 control chromosomes. c.853C>T has been reported in the literature in individuals affected with Late Onset Pompe Disease (Bali_2011, Carlier_2011, Kroos_2008, Nallamilli_2018, Orlikowski_2011), and in one reported case the GAA activity in the patients fibroblasts was <1% (Bali_2011). These data indicate that the variant is likely to be associated with disease. 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 likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 11, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 02, 2021

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.853C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 285 (p.Pro285Ser). The highest population minor allele frequency in gnomAD is 0.00009 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. REVEL (in silico meta predictor for missense changes) score = 0.757 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion. At least two patients had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PP4_Moderate). Two individuals with Pompe disease have been reported who are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.2237G>A (p.Trp746Ter)(PMID: 21484825)(0.5 points) or c.1354_1372del19 (PMID: 21550241)(0.5 points), Total 1 point (PM3). This variant results in <5% GAA activity when expressed in COS cells, and was classified as Class C ("less severe") by Kroos et al, 2012 (PMID:22644586), meeting the ClinGen LSD VCEP criteria for PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 281052, 1 star review status) with 5 submitters, two classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PP3, PM2_supporting, PM3, PS3_supporting. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the GAA protein (p.Pro285Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 21484825, 21550241). ClinVar contains an entry for this variant (Variation ID: 281052). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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: 14695532, 28196920). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jun 13, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		7.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.99
MPC		0.54
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886042086; hg19: chr17-78081516;