17-80112965-C-T

Variant names:

• chr17-80112965-C-T
• rs759518659
• NM_000152.5:c.1978C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PM2_Supporting PM3_Strong PM5 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1978C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 660 (p.Arg660Cys). At least 6 patients with clinical features consistent with Pompe disease have been reported with this variant; three with documented laboratory data showing deficiency of GAA in dried blood spot, or lymphocytes and muscle (PMID:17056254, 31193175, clinical laboratory data), and two reported to have deficient GAA activity and to be on enzyme replacement therapy on enzyme replacement therapy (PMID:25626711, 29122469, 31904026) (PP4_Moderate). Three of these patients are compound heterozygous, phase unknown, for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, either c.784G>A (p.Glu262Lys) (PMID 31193175), c.1082C>T (p.Pro361Leu) (clinical laboratory data), or c.546G>T (PMID:29124014) and another patient is homozygous (PMID:25626711) (PM3_Strong). An additional two patients are compound heterozygous for the variant and [c.1477C>T; c.2221G>A] ([p.Pro493Ser; p.Asp741Asn)] (PMID:29122469, 31904026), or c.1397T>G (p.Val466Gly) (PMID:17056254). The allelic data from the latter 2 patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/18006 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in <2% normal GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.966 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at this amino acid position, c.1979G>A (p.Arg660His) has been classified as pathogenic by the ClinGen LSD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 558604; 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 met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815561/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:10
• Conservation: PhyloP100: 5.98
• Publications: 14 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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 11 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.1978C>T	p.Arg660Cys	missense	Exon 14 of 20	NP_000143.2
	GAA	NM_001079803.3		c.1978C>T	p.Arg660Cys	missense	Exon 15 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.1978C>T	p.Arg660Cys	missense	Exon 14 of 20	NP_001073272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1978C>T	p.Arg660Cys	missense	Exon 14 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1978C>T	p.Arg660Cys	missense	Exon 15 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.1993C>T	p.Arg665Cys	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457932 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725038

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110822

Other (OTH) AF: 0.0000166 AC: 1 AN: 60208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000805303), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Glycogen storage disease, type II (6)
3	-	-	not provided (3)
1	-	-	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		Gain of catalytic residue at W661 (P = 0.0054)
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs759518659; hg19: chr17-78086764; COSMIC: COSV104403547; COSMIC: COSV104403547;