17-80108316-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000152.5(GAA):​c.982C>T​(p.Leu328Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

GAA
NM_000152.5 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000152.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAANM_000152.5 linkuse as main transcriptc.982C>T p.Leu328Phe missense_variant 6/20 ENST00000302262.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAAENST00000302262.8 linkuse as main transcriptc.982C>T p.Leu328Phe missense_variant 6/201 NM_000152.5 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2021This sequence change replaces leucine with phenylalanine at codon 328 of the GAA protein (p.Leu328Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GAA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;D
Eigen
Pathogenic
0.68
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.6
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
0.99
D;D
Vest4
0.87
MutPred
0.31
Loss of catalytic residue at L328 (P = 0.1433);Loss of catalytic residue at L328 (P = 0.1433);
MVP
0.99
MPC
0.50
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.75
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs1555599956; hg19: chr17-78082115; API