17-80113001-C-T

Variant names:

• chr17-80113001-C-T
• rs757111744
• NM_000152.5:c.2014C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2014C>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 672 (p.Arg672Trp). The variant has been reported in 5 patients with a diagnosis of Pompe disease supported by <10% normal GAA activity in muscle (PMID 9535769), <1% GAA activity in cultured fibroblasts (PMID 16917947), or GAA activity in the affected range in leukocytes or lymphocytes (PMID 22676651, 25526786) in addition to at least 5 patients stated to have symptoms consistent with Pompe disease and deficient GAA activity but values not provided (PMID 16917947, 21803581, 27692865)(PP4_Moderate). At least 5 patients are compound heterozygous for the variant and a variant in GAA classified as pathogenic by the ClinGen LSD VCEP, phase unknown - c.-32-13T>G (PMID 16917947), c.2385delG (PMID 21484825), c.1411_1414del (PMID 27692865), c.766_785delinsC (PMID 9535769), and c.1951_1952insT (clinical laboratory data) (PM3_Strong). The variant has also been reported in compound heterozygotes with c.1748C>T(p.Ser583Phe)(PMID 21484825), c.323G>A (p.Cys108Tyr) (PMID 25526786), c.1465G>A (p.Asp489Asn)(PMID 16917947), c.1703A>T (p.His568Leu)(PMID 17027861, 22676651), c.2474C>G (p.Pro825Arg)(PMID 30564623). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/29806 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in SV40-immortalized GAA-deficient fibroblasts revealed activity of <1% of the control value (PMID 9535769), and <2% activity in COS cells (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.9 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2015G>A (p.Arg672Gln)(see Table 1 in PMID 33578445) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (likely pathogenic without PM5 data from c.2014C>T (p.Arg672Trp) PM5_Supporting). c.2015G>T (p.Arg672Leu) has also been reported but has not yet met the criteria to be classified as pathogenic or likely pathogenic. There is a ClinVar entry for this variant (Variation ID: 188773; 2 star status) with 5 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: PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273939/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.949
• Publications: 15 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 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.2014C>T	p.Arg672Trp	missense	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2014C>T	p.Arg672Trp	missense	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2014C>T	p.Arg672Trp	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.2014C>T	p.Arg672Trp	missense	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2014C>T	p.Arg672Trp	missense	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2029C>T	p.Arg677Trp	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000829 AC: 2 AN: 241258 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1458210 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 725260

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111058

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		0.95
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.98		Loss of disorder (P = 0.0422)
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs757111744; hg19: chr17-78086800; COSMIC: COSV56412429; COSMIC: COSV56412429;