rs535644999

chr17-80109993-G-Achr17-80109993-G-Cchr17-80109993-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Strong

The NM_000152.5(GAA):c.1375G>A(p.Asp459Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,316 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D459H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:9
• Conservation: PhyloP100: 6.13

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80109994-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1483894.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 17-80109993-G-A is Pathogenic according to our data. Variant chr17-80109993-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 188480.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Pathogenic=2}. Variant chr17-80109993-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1375G>A	p.Asp459Asn	missense_variant	9/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1375G>A	p.Asp459Asn	missense_variant	9/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.0000719 AC: 18 AN: 250268 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1460938 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152378 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74520

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2 Uncertain:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Asp459Asn variant in GAA has been reported in 3 individuals (including 1 individual from China and 1 individual from Taiwan individual) with Glycogen Storage Disease II (PMID: 18458862, 21484825, 21757382), and has been reported as a VUS by EGL, Invitae, GeneDx, and Counsyl in ClinVar (Variation ID: 188480). This variant has been identified in 0.041% (14/34538) of Latino chromosomes, 0.005% (1/18370) of East Asian chromosomes, and 0.003% (3/112916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs535644999). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional computational prediction tools suggest the variant affects protein structure and stability (PMID: 29061980). However, the Aspartate (Asp) at position 459 is highly conserved in mammals and evolutionary distant species and one additional variant at the same position (p.Asp459His) has been reported as a VUS in ClinVar (Variation ID: 497673), raising the possibility that a change at this position may not be tolerated. The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in assays of relevant tissue (PMID: 18458862, 21757382). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 459 of the GAA protein (p.Asp459Asn). This variant is present in population databases (rs535644999, gnomAD 0.04%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18458862, 21484825, 21757382). ClinVar contains an entry for this variant (Variation ID: 188480). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 20, 2018	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 05, 2024	The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID: 21484825, 28302345). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 188480). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	A variant of uncertain significance has been identified in the GAA gene. The D459N variant in the GAA gene has previously been reported in association with late-onset Pompe disease in individuals who harbored a second missense variant in GAA, although the phase of these variants was not determined in these individuals (Wan et al., 2008; Yang et al., 2011, Bali et al., 2011). This variant is observed in 16/245730 (0.0065%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the D459N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 30, 2022

Variant summary: GAA c.1375G>A (p.Asp459Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250268 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (7.2e-05 vs 0.0042), allowing no conclusion about variant significance. c.1375G>A has been reported in the literature in multiple individuals affected with late onset Glycogen Storage Disease, Type 2 (Pompe Disease) (examples: Wan_2008, Bali_2011, Yang_GAA_2011 and Sawada_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.53
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.99	D;D
Vest4		0.89
MutPred		0.81		Loss of phosphorylation at Y455 (P = 0.1131);Loss of phosphorylation at Y455 (P = 0.1131);
MVP		1.0
MPC		0.51
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs535644999; hg19: chr17-78083792; COSMIC: COSV56412229; COSMIC: COSV56412229;