17-80107837-T-C

Variant names:

• chr17-80107837-T-C
• rs121907940
• NM_000152.5:c.896T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3 PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.896T>C variant in GAA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 299 (p.Leu299Pro). At least 4 individuals have been reported with this variant and either diagnosis of Pompe disease with ERT treatment or GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/unknown tissue (PMIDs 26622091, 26873529, 25626711,29422078). Another patient was homozygous for this variant and identified by newborn screening for Pompe disease (PMID:22133539). This meets the criteria for PP4_Moderate. This variant has been detected in at least 7 individuals with Pompe disease or identified by newborn screening for Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G (PMID:18757064, 26622091, 26873529). At least 1 individual was homozygous for the variant (PMID:22133539,25626711). Criteria for PM3 were met. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal synthesis and processing on Western blots leading the variant to be described as Class B (“potentially less severe”, indicating that this variant may impact protein function (PMID:18425781)(PS3). REVEL Score = 0.952 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 180144, 2 star review status) with 5 submitters classifying the variant as Pathogenic. 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, PP4_Moderate, PM3, PM2_Supporting, PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA273686/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.85
• 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: 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.896T>C	p.Leu299Pro	missense	Exon 5 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.896T>C	p.Leu299Pro	missense	Exon 6 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.896T>C	p.Leu299Pro	missense	Exon 5 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.896T>C	p.Leu299Pro	missense	Exon 5 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.896T>C	p.Leu299Pro	missense	Exon 6 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.896T>C	p.Leu299Pro	missense	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459968 Hom.: 0 Cov.: 56 AF XY: 0.00000275 AC XY: 2 AN XY: 726262

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111758

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Glycogen storage disease, type II (7)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		Gain of disorder (P = 0.0121)
MVP		1.0
MPC		0.68
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.98
Mutation Taster		=1/99	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: rs121907940; hg19: chr17-78081636;