rs577042191

Positions:

• chr17-80113351-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PM5

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2174G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 725 (p.Arg725Gln). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It only has been reported in one case with a positive newborn screening result for GAA-related disease, in which has concurrence of c.664 G>A (benign or likely benign) (PMID:23430949). Thus there is insufficient data to apply PP4 nor PM3. Another missense variant c.2173C>T (p.Arg725Trp) (PMID:8401535, 17616415, 19588081, 28648663, 30155607; ClinVar Variation ID: 4024), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. Thus PM5 is applied. There is a ClinVar entry for this variant (Variation ID: 555727, 1 star review status) with 2 submitters classifying the variant as Uncertain significance, and 2 submitters classifying it as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP3, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 3, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815636/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 9.81

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2174G>A	p.Arg725Gln	missense_variant	15/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2174G>A	p.Arg725Gln	missense_variant	15/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1431634 Hom.: 0 Cov.: 33 AF XY: 0.00000705 AC XY: 5 AN XY: 708902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000609

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 03, 2023	The NM_000152.5:c.2174G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 725 (p.Arg725Gln). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It only has been reported in one case with a positive newborn screening result for GAA-related disease, in which has concurrence of c.664 G>A (benign or likely benign) (PMID: 23430949). Thus there is insufficient data to apply PP4 nor PM3. Another missense variant c.2173C>T (p.Arg725Trp) (PMID: 8401535, 17616415, 19588081, 28648663, 30155607; ClinVar Variation ID: 4024), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. Thus PM5 is applied. There is a ClinVar entry for this variant (Variation ID: 555727, 1 star review status) with 2 submitters classifying the variant as Uncertain significance, and 2 submitters classifying it as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 3, 2023). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 725 of the GAA protein (p.Arg725Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 23430949). ClinVar contains an entry for this variant (Variation ID: 555727). 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. This variant disrupts the p.Arg725 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401535, 17616415, 19588081, 21550241). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at R725 (P = 0.0766);Gain of catalytic residue at R725 (P = 0.0766);
MVP		1.0
MPC		0.58
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.92

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: rs577042191; hg19: chr17-78087150;