NM_000152.5:c.953T>C

Variant names:

• chr17-80107894-T-C
• rs121907936
• NM_000152.5:c.953T>C

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM3 PM2_Supporting PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.953T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 318 (p.Met318Thr). Twelve probands with a diagnosis of Pompe disease were identified with this variant. At least 9 of them have GAA activity in the affected range in dried blood spots or <30% normal GAA activity in fibroblasts (PMIDs: 1652892, 19862843, 25139343, 30214072, 34357340, clinical laboratory data) with pseudodeficiency variants confirmed absent in three of these patients (clinical laboratory data) (PP4_Moderate). Of these patients, 10 are compound heterozygous for c.953T>C (p.Met318Thr) and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP; either c.2560C>T (p.Arg854Ter), confirmed in trans (PMID:1652892, 19862843), c.1979G>A (p.Arg660His), confirmed in trans by parental testing (clinical diagnostic laboratory); c.-32-13T>G, phase unknown (PMIDs: 29122469, 31904026, 32317649, clinical diagnostic laboratory) (at least 5 patients, 1 confirmed in trans) c.2481+102_2646+31del (p.Gly828_Asn882del), phase unknown (clinical diagnostic laboratory), c.1292_1295dupTGCA, phase unknown (PMID:30214072), or c.1082C>T (p.Pro361Leu), phase unknown (PMID:25139343). One patient is homozygous for the variant (PMID:34357340) (0.5 points) (PM3_Very Strong). Another patient is compound heterozygous for the variant and c.692+5G>T (PMID:29181627) but the allelic data from this patient will be used in the classification of c.692+5G>T and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Suporting, and therefore meets this criterion (PM2_Supporting). Functional studies involving expression of the variant in cultured cells indicate that the variant impacts function, resulting in <2% GAA activity (PMID:1652892, 19862843). The computational predictor REVEL gives a score of 0.89, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4021; 1 star review status) with 3 submitters classifying the variant as pathogenic, two as likley pathogenic and one as a variant of uncertain significance. With data from the published literature and a clinical laboratory, we find that the variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3.Classification approved by the ClinGen LSD VCEP on Sept. 6, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA116590/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: GAA NM_000152.5 missense, splice_region
• Scores: Splicing: ADA: 0.01787
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:1
• Conservation: PhyloP100: 6.08
• Publications: 24 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.953T>C	p.Met318Thr	missense splice_region	Exon 5 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.953T>C	p.Met318Thr	missense splice_region	Exon 6 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.953T>C	p.Met318Thr	missense splice_region	Exon 5 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.953T>C	p.Met318Thr	missense splice_region	Exon 5 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.953T>C	p.Met318Thr	missense splice_region	Exon 6 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.953T>C	p.Met318Thr	missense splice_region	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000423 AC: 10 AN: 236242 AF XY: 0.0000542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000504

Gnomad NFE exome AF: 0.0000659

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000412 AC: 60 AN: 1455848 Hom.: 0 Cov.: 52 AF XY: 0.0000442 AC XY: 32 AN XY: 724088

African (AFR) AF: 0.0000599 AC: 2 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5104

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1110616

Other (OTH) AF: 0.0000665 AC: 4 AN: 60110

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152098 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74322

African (AFR) AF: 0.000121 AC: 5 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67988

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

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (10)
2	1	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.86		Loss of stability (P = 0.0016)
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.92
gMVP		0.87
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.018
dbscSNV1_RF	Benign	0.33
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: rs121907936; hg19: chr17-78081693;