17-80110055-G-C

Variant names:

• chr17-80110055-G-C
• rs796051877
• NM_000152.5:c.1437G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1437G>C (p.Lys479Asn) variant in GAA alters the last nucleotide of exon 9. The computational predictor SpliceAI predicts that this variant may impact splicing (score for loss of the intron 10 donor splice site = 0.37; possible donor gain 175 bp downstream) (PP3). The computational predictor REVEL gives a score of 0.608 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Three probands have been reported with the variant, all with infantile onset Pompe disease and documented values showing GAA activity in the affected range. One of the patients was on enzyme replacement therapy (PMID:18458862, 31510962, 32711049) (PP4_Moderate). Two probands are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (ClinVar Variation ID: 4029; SCV002032138.1) (PMID:18458862, 32711049, 2 x 0.5 points) (PM3). Another proband is compound heterozygous for the variant, confirmed in trans with c.1327-2A>G (PMID:31510962). The allelic data from this patient will be used in the assessment of the splicing variant and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Other variants of the same splice region have been reported in patients with Pompe disease including c.1437+1G>A (likely pathogenic based on classification by the ClinGen LD VCEP); and c.1437+2T>C (pathogenic based on classification by the ClinGen LD VCEP). However, the SpliceAI score for donor loss is lower than for these other variants, and therefore PS1 was not applied at any strength (see Table 2, PMID:37352859). There is a ClinVar entry for the variant (Variation ID: 3241647). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401366671/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 34)
• Consequence: GAA NM_000152.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.20
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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.1437G>C	p.Lys479Asn	missense splice_region	Exon 9 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1437G>C	p.Lys479Asn	missense splice_region	Exon 10 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1437G>C	p.Lys479Asn	missense splice_region	Exon 9 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.1437G>C	p.Lys479Asn	missense splice_region	Exon 9 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1437G>C	p.Lys479Asn	missense splice_region	Exon 10 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1437G>C	p.Lys479Asn	missense splice_region	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Glycogen storage disease, type II (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	D
Vest4		0.75
MutPred		0.87		Loss of methylation at K479 (P = 0.0038)
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.79
gMVP		0.78
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796051877; hg19: chr17-78083854;