chr17-80118308-A-T

Variant names:

• chr17-80118308-A-T
• rs951742543
• NM_000152.5:c.2597A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000152.5(GAA):​c.2597A>T​(p.Glu866Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,590,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. E866A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.0200

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset, glycogen storage disease due to acid maltase deficiency, infantile onset.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20680666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.2597A>T	p.Glu866Val	missense_variant	Exon 18 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2597A>T	p.Glu866Val	missense_variant	Exon 18 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000853 AC: 2 AN: 234558 AF XY: 0.00000791

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000904 AC: 13 AN: 1438624 Hom.: 0 Cov.: 35 AF XY: 0.00000842 AC XY: 6 AN XY: 712754

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.00 AC: 0 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24432

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 83586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1098578

Other (OTH) AF: 0.00 AC: 0 AN: 59218

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Uncertain:3

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 866 of the GAA protein (p.Glu866Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456410). 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 not expected to disrupt GAA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GAA p.Glu866Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs951742543) and ClinVar (classified as uncertain significance by Invitae for glycogen storgae disease type II). The variant was identified in control databases in 2 of 234558 chromosomes at a frequency of 0.000008527 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 2 of 106148 chromosomes (freq: 0.000019), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Glu866 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

May 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19343043, 22253258) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.73	D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.88	L;L
PhyloP100		-0.020
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		0.022	B;B
Vest4		0.27
MVP		0.83
MPC		0.13
ClinPred		0.065	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.83

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

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Other links and lift over

dbSNP: rs951742543; hg19: chr17-78092107;