chr17-80108495-C-T

Variant names:

• chr17-80108495-C-T
• rs755253527
• NM_000152.5:c.1082C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3_Moderate PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1082C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 361 (p.Pro361Leu). This variant has been reported in at least 13 individuals with clinical symptoms consistent with Pompe disease including 6 individuals with documented laboratory values showing deficiency of GAA activity below normal range in leukocytes or <1% activity in fibroblasts or another tissue, many of whom were also reported to be showing improvement on enzyme replacement therapy and/or had specific features reported for infantile onset Pompe disease including cardiomyopathy and motor delay (PMID:21484825, 25139343, 25526786, 26497565, 27344650, 31439017, 31915562) and another patient with features specific for infantile onset Pompe disease, on enzyme replacement therapy (PMID:30023291). Pseudodeficiency variants, c.1726G>A and c.2065G>A, were reported to be absent in at least one of these patients (PMID:25526786) (PP4_Moderate). Of the patients reported with this variant, four are compound heterozygous for the variant and another variant in GAA classified as pathogenic by the ClinGen LSD VCEP including c.784G>A (p.Glu262Lys) (PMID:31915562; confirmed in trans by parental DNA testing) and c.1933G>A (p.Asp645Asn) (PMID:26497565, 27344650; phase unknown), c.1935C>A (p.Asp645Glu) (PMID:31439017; phase unknown), and c.2238G>C (p.Trp746Cys) (PMID:35123860; phase unknown). In addition, two homozygotes have been reported (PMID:30023291, 31931849), one of whom was identified by next generation sequencing panel for limb girdle muscle weakness, and not counted due to no report of follow up enzyme studies to confirm diagnosis of Pompe disease (PMID:31931849) (PM3_Strong). Additional patients have been reported with the variant in compound heterozygosity with another variant including c.503G>C (p.Arg168Pro) (PMID:25526786), c.953T>C (p.Met318Thr) (PMID:25139343), c.1309C>T (p.Arg437Cys) (PMID:12601120, 27692865), c.1432G>A (p.Gly478Arg) (PMID:25213570), c.1979G>A (p.Arg660His) (PMID:21484825), and c.1551+1G>C (PMID:16917947). In these cases, the allelic data will be used in the assessment of the second variant and was not applied to PM3 here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells and GAA deficient fibroblasts, this variant resulted in <4% wild type GAA activity in three different studies (PMID:12601120, 19862843, 22644586) and showed evidence of abnormal synthesis and processing on Western blot (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at the same codon, c.1082C>A (p.Pro361Arg) has been reported (PMID:31076647). The classification of p.Pro163Leu will be used in the assessment of p.Pro361Arg and, therefore, PM5 is not applied here. There is a ClinVar entry for this variant (Variation ID: 403712, 2 star review status) with four submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815163/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 7.39
• Publications: 29 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.
• 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.1082C>T	p.Pro361Leu	missense	Exon 7 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1082C>T	p.Pro361Leu	missense	Exon 8 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1082C>T	p.Pro361Leu	missense	Exon 7 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.1082C>T	p.Pro361Leu	missense	Exon 7 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1082C>T	p.Pro361Leu	missense	Exon 8 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1082C>T	p.Pro361Leu	missense	Exon 7 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249370 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460752 Hom.: 0 Cov.: 38 AF XY: 0.00000550 AC XY: 4 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000260 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of catalytic residue at P361 (P = 0.0183)
MVP		0.97
MPC		0.55
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.94
Mutation Taster		=20/80	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: rs755253527; hg19: chr17-78082294;