rs914396317

Variant names:

• chr17-80112680-C-G
• rs914396317
• NM_000152.5:c.1857C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80112680-C-G
• chr17-80112680-C-T

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM2_Supporting PM3 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1857C>G variant in GAA is predicted to result in the substitution of serine by arginine at amino acid 619 (p.Ser619Arg).This variant has been reported in at least 10 patients with features consistent with Pompe disease including individuals with clinical symptoms of Pompe disease and documented laboratory data showing GAA activity below the normal reference range or <10% in relevant tissues (PMID:14643388, 17092519, 29124014, 21984055, 23884227), and additional patients without GAA activity reported but on enzyme replacement therapy (PMID:25213570, 29869463) (PP4_Moderate). Five patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.1579_1580del (p.Arg527GlyfsTer3), confirmed in trans (PMID:29869463); c.1156C>T (p.Gln386Ter), phase unknown (PMID:23884227); c.1309C>T (p.Arg437Cys), phase unknown (PMID:29124014); c.1798C>T (p.Arg600Cys), phase unknown (PMID:29124014); and c.1735G>A (p.Glu579Lys), phase unknown (PMID:29124014); and at least three are homozygous for the variant (PMID:14643388, 29124014) (maximum allowed = 2 x 0.5 points = 1 point). Additional patients have been reported who are compound heterozygous for the variant and either c.875A>G (p.Tyr292Cys) (PMID:23884227, 25213570), or c.2015G>A (p.Arg672Gln) (PMID:17092519). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Finally, additional patients may also carry the variant but were not included because the cDNA change for the variant was not reported (PMID:17805474, 18495398, 21676566) (PM3_Very Strong). When expressed in COS cells in two seprate function, studies, the variant results in <2% GAA activity compared to wild type (PMIDs: 14643388, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.795 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 550825). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on December 6, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369658/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 2.04
• Publications: 8 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: Pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1857C>G	p.Ser619Arg	missense	Exon 13 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1857C>G	p.Ser619Arg	missense	Exon 14 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1857C>G	p.Ser619Arg	missense	Exon 13 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.1857C>G	p.Ser619Arg	missense	Exon 13 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1857C>G	p.Ser619Arg	missense	Exon 14 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1872C>G	p.Ser624Arg	missense	Exon 13 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458978 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 725668

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111346

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease, type II (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of MoRF binding (P = 0.0114)
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs914396317; hg19: chr17-78086479;