rs113085339

Variant names:

• chr17-80105878-C-G
• rs113085339
• NM_000152.5:c.676C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA198772/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.663
• Publications: 9 publications found

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]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.676C>G	p.Leu226Val	missense	Exon 3 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.676C>G	p.Leu226Val	missense	Exon 4 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.676C>G	p.Leu226Val	missense	Exon 3 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.676C>G	p.Leu226Val	missense	Exon 3 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.676C>G	p.Leu226Val	missense	Exon 4 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.676C>G	p.Leu226Val	missense	Exon 3 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000594 AC: 144 AN: 242408 AF XY: 0.000553

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000277 AC: 400 AN: 1445942 Hom.: 3 Cov.: 34 AF XY: 0.000306 AC XY: 220 AN XY: 718546

African (AFR) AF: 0.00740 AC: 247 AN: 33362

American (AMR) AF: 0.000695 AC: 31 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43722

Middle Eastern (MID) AF: 0.000794 AC: 4 AN: 5038

European-Non Finnish (NFE) AF: 0.0000659 AC: 73 AN: 1107440

Other (OTH) AF: 0.000683 AC: 41 AN: 60050

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152368 Hom.: 3 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74514

African (AFR) AF: 0.00623 AC: 259 AN: 41598

American (AMR) AF: 0.00105 AC: 16 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.00198

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type II (5)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GAA-related disorder (1)
-	-	1	not provided (1)
-	-	1	Ventricular fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.66
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.25	T
Polyphen		0.0090	B
Vest4		0.11
MVP		0.91
MPC		0.11
ClinPred		0.0081	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.51
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113085339; hg19: chr17-78079677;