rs886042086

Variant names:

• chr17-80107717-C-T
• rs886042086
• NM_000152.5:c.853C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.853C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 285 (p.Pro285Ser). The highest population minor allele frequency in gnomAD is 0.00009 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. REVEL (in silico meta predictor for missense changes) score = 0.757 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion. At least two patients had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PP4_Moderate). Two individuals with Pompe disease have been reported who are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.2237G>A (p.Trp746Ter)(PMID:21484825)(0.5 points) or c.1354_1372del19 (PMID:21550241)(0.5 points), Total 1 point (PM3). This variant results in <5% GAA activity when expressed in COS cells, and was classified as Class C ("less severe") by Kroos et al, 2012 (PMID:22644586), meeting the ClinGen LSD VCEP criteria for PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 281052, 1 star review status) with 5 submitters, two classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely 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): PP4_moderate, PP3, PM2_supporting, PM3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603793/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.000074 (0 hom., cov: 34)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 7.79
• Publications: 9 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 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.853C>T	p.Pro285Ser	missense	Exon 4 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.853C>T	p.Pro285Ser	missense	Exon 5 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.853C>T	p.Pro285Ser	missense	Exon 4 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.853C>T	p.Pro285Ser	missense	Exon 4 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.853C>T	p.Pro285Ser	missense	Exon 5 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.853C>T	p.Pro285Ser	missense	Exon 4 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 10 AN: 135790 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202738 AF XY: 0.00000906

Gnomad AFR exome AF: 0.0000679

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000736 AC: 10 AN: 135790 Hom.: 0 Cov.: 34 AF XY: 0.0000457 AC XY: 3 AN XY: 65688

African (AFR) AF: 0.000269 AC: 10 AN: 37132

American (AMR) AF: 0.00 AC: 0 AN: 13598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3202

East Asian (EAS) AF: 0.00 AC: 0 AN: 4722

South Asian (SAS) AF: 0.00 AC: 0 AN: 4088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61504

Other (OTH) AF: 0.00 AC: 0 AN: 1782

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	1	-	Glycogen storage disease, type II (8)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.54
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.86
Mutation Taster		=8/92	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: rs886042086; hg19: chr17-78081516;