rs778418246

Variant names:

• chr17-80113002-G-A
• rs778418246
• NM_000152.5:c.2015G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80113002-G-A
• chr17-80113002-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PM3_Strong PS3_Supporting PM5_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2015G>A variant in GAA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 672 (p.Arg672Gln). At least 8 probands with Pompe disease have been reported with this variant, including 4 probands and one sibling with published data showing GAA activity below the normal range in muscle or cultured fibroblasts (PMID:9535769, 17092519, 33578445), three of whom also showed clinical improvement on enzyme replacement therapy (PMID 33578445)(PP4_Moderate). Five probands are homozygous for the variant (PMIDs 9535769, 25712382, 28937052, 33578445). Two probands are compound heterozygous for the variant and a pathogenic variant in GAA; the second variant is either c.118C>T (p.Arg40Ter)(ClinVar SCV001371737.1)(phase unknown), or c.1857C>G (p.Ser619Arg)(phase unknown)(PM3_Strong). Another proband is heterozygous for the variant with the second variant unidentified (PMID 11053688). When generated by site-directed mutagenesis and expressed in SV40-immortalized GAA deficient fibroblasts or COS cells, the variant resulted in very low (<2%) residual GAA activity (PMID 9535769, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.955 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in gnomAD is 0.0001107 (East Asian) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting (PM2_Supporting). Two other missense variants at the same amino acid position, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported in patients with Pompe disease, suggesting that this residue may be important in GAA function. Two other missense variants, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported at the same amino acid position; c.2014C>T (p.Arg672Trp) has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. PM5_Supporting is applied here because c.2014C>T (p.Arg672Trp) is only likely pathogenic without PM5 data from c.2015G>A (p.Arg672Gln), thus avoiding circular logic (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 371126, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815566/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 9.86
• Publications: 18 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_pathogenic. The variant received 10 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.
• PM5: 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.2015G>A	p.Arg672Gln	missense	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2015G>A	p.Arg672Gln	missense	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2015G>A	p.Arg672Gln	missense	Exon 14 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.2015G>A	p.Arg672Gln	missense	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2015G>A	p.Arg672Gln	missense	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2030G>A	p.Arg677Gln	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 241788 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458548 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725430

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39634

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52030

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111192

Other (OTH) AF: 0.0000498 AC: 3 AN: 60246

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.1665)
MVP		1.0
MPC		0.58
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs778418246; hg19: chr17-78086801;