rs786204680

Variant names:

• chr17-80108811-C-T
• rs770610356
• NM_000152.5:c.1309C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80108811-C-T
• chr17-80108811-C-A

Variant summary

Our verdict is 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.1309C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 437 (p.Arg437Cys). This variant has been reported in at least 16 East Asian individuals with late onset Pompe disease (PMID:34356580) including 11 individuals with documented laboratory values reporting GAA activity <10% normal in muscle or skin fibroblasts or in the affected range in a clinically validated dried blood spot assay and/or histological features consistent with Pompe disease in muscle, and/or on enzyme replacement therapy for Pompe disease (PMID 22521436, 29786057, 27692865, 30360039)(PP4_Moderate). Ten individuals are reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including one confirmed in trans, c.1082C>T (p.Pro361Leu) (PMID:12601120), and 9 phase unknown, c.796C>T (p.Pro266Ser) (PMID:25526786), c.1082C>T (p.Pro361Leu) (PMID:27692865), c.1316T>A (p.Met439Lys) (PMID:25388776), c.1822C>T (p.Arg608Ter) (PMID:30360039), c.1978C>T (p.Arg600Cys) (PMID:29124014, 3 probands), c.2238G>C (p.Trp746Cys) (PMID:27692865), c.2297A>G (p.Tyr766Cys) (PMID:29124014) (PM3_VeryStrong). The variant has also been reported in compound heterozygosity with c.1544T>A (p.Met515Lys) (PMID:24190153), c.1562A>T (p.Glu521Val) (PMID:29786057), c.1857C>G (p.Ser619Arg) (PMID:291240140, c.2051C>A (p.Pro684Gln) (PMID:29451150), c.2177C>G (p.Pro726Arg) (PMID:29124014), and c.2297A>C (p.Tyr766Ser) (PMID:22521436). The allelic data from these patients will be used in the classification of the second variant and is not included here in order to avoid circular logic. Additional patients have also been reported but the data was not included because the cDNA sequences of the variants was not included (PMID:18495398, 21471980, 21704464). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (2/21914 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cells showed no detectable GAA enzyme activity, and another study showed abnormal synthesis and processing of GAA when the variant was expressed in COS cells, indicating that this variant may impact protein function (PMID:12601120, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.782, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A novel variant at the same amino acid position, c.1310G>A (p.Arg437His) has been reported in a patient with Pompe disease (PMID:25681614) but has not yet been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, PM5 is not applied. There is a ClinVar entry for this variant (Variation ID: 189082, 2 star review status) with 6 submitters classifying the variant as pathogenic and two as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274356/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 1.49
• Publications: 19 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: 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.1309C>T	p.Arg437Cys	missense	Exon 8 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1309C>T	p.Arg437Cys	missense	Exon 9 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1309C>T	p.Arg437Cys	missense	Exon 8 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.1309C>T	p.Arg437Cys	missense	Exon 8 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1309C>T	p.Arg437Cys	missense	Exon 9 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1309C>T	p.Arg437Cys	missense	Exon 8 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00000460 AC: 1 AN: 217456 AF XY: 0.00000845

Gnomad AFR exome AF: 0.0000757

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 AF: 0.00000830 AC: 12 AN: 1445940 Hom.: 0 Cov.: 36 AF XY: 0.00000835 AC XY: 6 AN XY: 718182

African (AFR) AF: 0.000120 AC: 4 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 42548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.0000515 AC: 2 AN: 38854

South Asian (SAS) AF: 0.00 AC: 0 AN: 84282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1104830

Other (OTH) AF: 0.00 AC: 0 AN: 59724

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000965 AC: 4 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Glycogen storage disease, type II (11)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.62
MutPred		0.89		Loss of disorder (P = 0.0531)
MVP		1.0
MPC		0.56
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.82
gMVP		0.84
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770610356; hg19: chr17-78082610;