17-80104851-C-T

Variant names:

• chr17-80104851-C-T
• rs534192892
• NM_000152.5:c.265C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID:28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance 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): PP3.(Classification approved by the ClinGen LSD VCEP on December 20, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814832/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:8 O:1
• Conservation: PhyloP100: 2.44
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: 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.265C>T	p.Arg89Cys	missense	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.265C>T	p.Arg89Cys	missense	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.265C>T	p.Arg89Cys	missense	Exon 2 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.265C>T	p.Arg89Cys	missense	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.265C>T	p.Arg89Cys	missense	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.265C>T	p.Arg89Cys	missense	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000250 AC: 62 AN: 248200 AF XY: 0.000334

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1460632 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 136 AN XY: 726616

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111906

Other (OTH) AF: 0.000116 AC: 7 AN: 60380

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000542 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	4	-	Glycogen storage disease, type II (6)
-	2	-	not provided (2)
-	2	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		2.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.91		Loss of phosphorylation at S88 (P = 0.0837)
MVP		0.97
MPC		0.63
ClinPred		0.81	D
GERP RS		4.0
Varity_R		0.91
gMVP		0.89
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs534192892; hg19: chr17-78078650;