rs121907938

Variant names:

• chr17-80113350-C-T
• rs121907938
• NM_000152.5:c.2173C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80113350-C-T
• chr17-80113350-C-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2173C>T variant in GAA is a missense variant predicted to cause substitution of Arg by Trp at amino acid 725 (p.Arg725Trp). This variant is present in gnomAD V2.1.1 with the highest population minor allele frequency of 0.00077 (7/9058 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen LSD VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. This variant results in 6.5% GAA activity when expressed in COS cells (PMID:8401535), meeting the ClinGen LSD VCEP specifications for PS3. This variant has been detected in at least 12 individuals with Pompe disease. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant including 2 with c.573C>A-pathogenic (PMID:30155607), 1 with ex18 deletion-pathogenic (PMID:28648663), 3 with c.-32-13T>G-pathogenic (PMID:27711114, 17616415), 1 with c.-32-3C>A-likely pathogenic (PMID:19588081), 2 with c.1076-1G>C pathogenic variants (PMID:17616415). 1 individual was homozygous for the variant (PMID:27711114). A total of 4.25 points were awarded. Thus meets PM3-Very Strong. At least 4 individuals have been reported with this variant and GAA activity <10% normal in leukocytes/muscle samples or <30% normal in cultured fibroblasts. Patient 5 (PMID:21550241) has 0.2% normal GAA activity in fibroblast. Patient 3 has 1.1% normal GAA activity in fibroblasts, patient 15 has 5.2% normal GAA activity in fibroblasts (PMID:17616415). Patient 1 (PMID:3865697) has GAA activity in affected range in muscle, cultured fibroblasts, and leucocytes when compared to the laboratory’s control range. This meets the criteria for PP4. There is a ClinVar entry for this variant (Variation ID: 4024; 2 star review status) with 9 submitters classifying the variant as pathogenic with no conflict. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PS3-supporting, PM2-supporting, PM3-very strong, PP3, and PP4-moderate.(Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116598/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.17
• Publications: 19 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.2173C>T	p.Arg725Trp	missense	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2173C>T	p.Arg725Trp	missense	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2173C>T	p.Arg725Trp	missense	Exon 15 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.2173C>T	p.Arg725Trp	missense	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2173C>T	p.Arg725Trp	missense	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2188C>T	p.Arg730Trp	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000389 AC: 8 AN: 205684 AF XY: 0.00000902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000684

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000223

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 21 AN: 1432526 Hom.: 0 Cov.: 33 AF XY: 0.00000987 AC XY: 7 AN XY: 709352

African (AFR) AF: 0.00 AC: 0 AN: 33008

American (AMR) AF: 0.00 AC: 0 AN: 41556

Ashkenazi Jewish (ASJ) AF: 0.000356 AC: 9 AN: 25270

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38336

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1096412

Other (OTH) AF: 0.0000677 AC: 4 AN: 59074

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000831 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
2	-	-	not provided (2)
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at A724 (P = 0.0129)
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.96
Mutation Taster		=0/100	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: rs121907938; hg19: chr17-78087149; COSMIC: COSV56408105; COSMIC: COSV56408105;