rs892129065

Variant names:

• chr17-80110953-C-A
• rs892129065
• NM_000152.5:c.1564C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80110953-C-A
• chr17-80110953-C-G
• chr17-80110953-C-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):​c.1564C>A​(p.Pro522Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000617643: P522 is located at the end of a beta-strand before and alpha-helical region of the alpha-glucosidase protein and replacement of the Proline at this position may cause misfolding of the protein (Pittis et al., 2008). Furthermore a missense variant at the same residue (P522A) have also been reported in a patient with GSDII, and functional analysis of this other variant found that it is associated with no residual enzyme activity (Pittis et al., 2008).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P522S) has been classified as Likely pathogenic. The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.02
• Publications: 3 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617643: P522 is located at the end of a beta-strand before and alpha-helical region of the alpha-glucosidase protein and replacement of the Proline at this position may cause misfolding of the protein (Pittis et al., 2008). Furthermore a missense variant at the same residue (P522A) have also been reported in a patient with GSDII, and functional analysis of this other variant found that it is associated with no residual enzyme activity (Pittis et al., 2008).
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80110953-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 972746.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease due to acid maltase deficiency, late-onset.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-80110953-C-A is Pathogenic according to our data. Variant chr17-80110953-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1564C>A	p.Pro522Thr	missense	Exon 11 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1564C>A	p.Pro522Thr	missense	Exon 12 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1564C>A	p.Pro522Thr	missense	Exon 11 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.1564C>A	p.Pro522Thr	missense	Exon 11 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1564C>A	p.Pro522Thr	missense	Exon 12 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1579C>A	p.Pro527Thr	missense	Exon 11 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461636 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		6.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Loss of disorder (P = 0.1102)
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.95
Mutation Taster		=6/94	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: rs892129065; hg19: chr17-78084752;