17-80110055-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Moderate PM3 PP3 PM2_Supporting

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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1437G>C	p.Lys479Asn	missense_variant, splice_region_variant	Exon 9 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1437G>C	p.Lys479Asn	missense_variant, splice_region_variant	Exon 9 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2

Feb 20, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.96	D;D
Vest4		0.75
MutPred		0.87		Loss of methylation at K479 (P = 0.0038);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78083854;