rs765362308

Variant names:

• chr17-80112056-C-G
• rs765362308
• NM_000152.5:c.1710C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80112056-C-G
• chr17-80112056-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PS3_Moderate PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. At least three individuals have been reported with this variant and documented GAA activity in the affected range and/or were reported to be on enzyme replacement therapy for Pompe disease (PMID:17151339, 22538254, 29122469, 32248831) (PP4_Moderate). This variant was found in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1), phase unconfirmed, in at least one patient with Pompe disease (PMID:22538254, 22658377, 29122469, 31193175)(0.5 points), and confirmed in trans in a patient with c.953T>C (p.Met318Thr) (ClinVar Variation ID: 4021; SCV002583364.1) (PMID:36636589) (1 point). Another patient with the variant, along with with c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=) has been reported (PMID:32248831). While the allelic data from the latter patient is likely supportive of pathogenicity for c.1710C>G (p.Asn570Lys), it is not included here because the impact of p.Leu641= is unknown (Total 1.5 points) (PM3). Functional assays support a deleterious effect of this variant. When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LD VCEP threshold for PP3 (>0.7) but higher than the LD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. There is a ClinVar entry for this variant (Variation ID: 555153). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel. GAA-specific GAA-specific ACMG/AMP criteria met (Specifications Version 2.0): PS3_Moderate, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369044/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.49
• Publications: 10 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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.
• 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.1710C>G	p.Asn570Lys	missense	Exon 12 of 20	NP_000143.2
	GAA	NM_001079803.3		c.1710C>G	p.Asn570Lys	missense	Exon 13 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.1710C>G	p.Asn570Lys	missense	Exon 12 of 20	NP_001073272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1710C>G	p.Asn570Lys	missense	Exon 12 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1710C>G	p.Asn570Lys	missense	Exon 13 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.1725C>G	p.Asn575Lys	missense	Exon 12 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ 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 AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	1	-	Glycogen storage disease, type II (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.95	P
Vest4		0.87
MutPred		0.89		Gain of ubiquitination at N570 (P = 0.0351)
MVP		0.97
MPC		0.54
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.94
gMVP		0.86
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 1

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

Other links and lift over

dbSNP: rs765362308; hg19: chr17-78085855;