rs370950728

Variant names:

• chr17-80105857-G-A
• rs370950728
• NM_000152.5:c.655G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80105857-G-A
• chr17-80105857-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PP4 PM3_Strong PS3 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.655G>A (p.Gly219Arg), has been reported in at least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, including c.-32-13T>G (PMID 21550241, 24844452), c.169C>T (p.Gln57Ter) (PMID 29124014), or c.2560C>T (p.Arg854Ter)(PMID 23266370), and one is homozygous for the variant (PMID 25139343). This in trans data meets PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 in the African population, meeting PM2. When it was expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843), meeting PS3. The score for the REVEL in silico meta-predictor, 0.872, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID 189065; 2 star review status) with four submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274334/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:1
• Conservation: PhyloP100: 9.71
• Publications: 40 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 12 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.655G>A	p.Gly219Arg	missense	Exon 3 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.655G>A	p.Gly219Arg	missense	Exon 4 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.655G>A	p.Gly219Arg	missense	Exon 3 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.655G>A	p.Gly219Arg	missense	Exon 3 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.655G>A	p.Gly219Arg	missense	Exon 4 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.655G>A	p.Gly219Arg	missense	Exon 3 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 244972 AF XY: 0.00000750

Gnomad AFR exome AF: 0.0000620

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453526 Hom.: 0 Cov.: 57 AF XY: 0.00000830 AC XY: 6 AN XY: 723044

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 47046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110638

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000601 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	1	-	Glycogen storage disease, type II (9)
3	-	-	not provided (3)
1	-	-	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.78		Gain of MoRF binding (P = 0.068)
MVP		0.99
MPC		0.39
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.94
Mutation Taster		=5/95	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: rs370950728; hg19: chr17-78079656;