rs1555599667

chr17-80107660-C-Achr17-80107660-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000152.5(GAA):c.796C>A(p.Pro266Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. P266S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.00400

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr17-80107660-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556117.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.122752815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.796C>A	p.Pro266Thr	missense_variant	4/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.796C>A	p.Pro266Thr	missense_variant	4/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Jun 30, 2022

The NM_000152.5:c.796C>A variant in GAA is a missense variant predicted to cause substitution of proline by threonine at amino acid 266 (p.Pro266Thr). One patient with a diagnosis of Pompe disease has been reported who is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2237G>A (p.Trp746Ter) (PMID: 29451150) (PM3_Supporting). Two other missense changes, c.796C>T (p.Pro266Ser) and c.797C>T (p.Pro266Leu) at the same amino acid residue have been reported. The first, c.796C>T (p.Pro266Ser), has been classified as likely pathogenic by the ClinGen LSD VCEP. The second variant, c.797C>T (p.Pro266Leu), has not been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5_Supporting). The computational predictor REVEL gives a score of 0.262 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is no ClinVar entry for this variant. In summary, this variant meet the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP codes met, based on the specifications of the ClinGen LSD VCEP (Specifications version 2.0): PM2_Supporting, PM3_Supporting, PM5_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	14
Dann	Benign	0.66
DEOGEN2	Benign	0.0089	T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T;.;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.018	.;B;B
Vest4		0.43, 0.43
MutPred		0.42		Gain of catalytic residue at P266 (P = 0.0155);Gain of catalytic residue at P266 (P = 0.0155);Gain of catalytic residue at P266 (P = 0.0155);
MVP		0.92
MPC		0.14
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78081459;