rs1555599667

Positions:

• chr17-80107660-C-A
• chr17-80107660-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2_Supporting BP4 PM3_Supporting PM5_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401363493/MONDO:0009290/010

• 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 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.796C>A	p.Pro266Thr	missense_variant	4/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.796C>A	p.Pro266Thr	missense_variant	4/20	1	NM_000152.5	ENSP00000305692.3

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
MutationAssessor	Benign	1.1	.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.080	.;N;N
REVEL	Benign	0.26
Sift	Benign	0.51	.;T;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;