17-80107894-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.953T>C(p.Met318Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000423 in 1,607,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M318K) has been classified as Likely pathogenic.

• 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:11 U:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 5) in uniprot entity LYAG_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr17-80107894-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558700.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 17-80107894-T-C is Pathogenic according to our data. Variant chr17-80107894-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4021.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80107894-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.953T>C	p.Met318Thr	missense_variant, splice_region_variant	5/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.953T>C	p.Met318Thr	missense_variant, splice_region_variant	5/20	1	NM_000152.5	P1

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

GnomAD3 exomes AF: 0.0000423 AC: 10 AN: 236242 Hom.: 0 AF XY: 0.0000542 AC XY: 7 AN XY: 129082

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 SAS exome AF: 0.0000336

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

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000665

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

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Met318Thr variant in GAA has been reported in 2 individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343), and has also been reported pathogenic by OMIM, likely pathogenic by Integrated Genetics, and a VUS by EGL Genetic Diagnostics in ClinVar (Variation ID: 4021). This variant has been identified in 0.009% (2/23234) of African chromosomes and 0.006% (7/121686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907936). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with a minigene assay provide some evidence that the p.Met318Thr variant may eliminate GAA activity (PMID: 1652892). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. However, the Methionine (Met) at position 318 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. Two additional variants at the same position, p.Met318Lys and p.Met318Leu, have been reported as VUS in ClinVar but p.Met318Lys is a likely pathogenic variant, slightly increasing the likelihood that the p.Met318Thr variant is pathogenic (Variation ID: 558700, 290616; PMID: 21484825, 22644586). This variant has been reported in combination with a reported likely pathogenic variant and a variant reported to cause NMD, and in individuals with Glycogen Storage Disease II (PMID: 1652892, 25139343). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM5_Supporting, PP3, PP4 (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 06, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 16, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Therapies Laboratory, Murdoch University	Jan 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2022	Variant summary: GAA c.953T>C (p.Met318Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 236242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.2e-05 vs 0.0042), allowing no conclusion about variant significance. c.953T>C has been reported in the literature in several individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (ie. Zhong_1991, Flanagan_2009, Mori_2017, Loscher_2018, Kazi_2019). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in <10% of normal activity (Zhong_1991, Flanagan_2009). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six labs classified as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 318 of the GAA protein (p.Met318Thr). This variant is present in population databases (rs121907936, gnomAD 0.009%). This missense change has been observed in individuals with Pompe disease (PMID: 1652892, 19862843, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 4021). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GAA function (PMID: 1652892, 19862843). This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21484825), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect with <2% residual GAA enzyme activity (Zhong et al., 1991; Flanagan et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19862843, 21228398, 29181627, 30214072, 31254424, 22253258, 19343043, 34357340, 25139343, 31342611, 31086307, 29122469, 30155607, 31904026, 32317649, 34576242, 1652892) -

Glycogen storage disease type II, infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.86		Loss of stability (P = 0.0016);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121907936; hg19: chr17-78081693;