rs121907936

chr17-80107894-T-Achr17-80107894-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>A(p.Met318Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M318T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense, splice_region
• Scores: Splicing: ADA: 0.01787
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 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-C is described in ClinVar as [Pathogenic]. Clinvar id is 4021.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 17-80107894-T-A is Pathogenic according to our data. 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. Variant chr17-80107894-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.953T>A	p.Met318Lys	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>A	p.Met318Lys	missense_variant, splice_region_variant	5/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2022	Variant summary: GAA c.953T>A (p.Met318Lys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 236242 control chromosomes (gnomAD). c.953T>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease database, Kroos_2008, Bali_2011, Sun_2018). These data indicate that the variant may be associated with disease. Kroos_2012 has shown that the variant results in 3.2% enzymatic activity in cell culture. Four ClinVar submitters, including one expert panel, have assessed the variant since 2014: three, including the expert panel, classified the variant as likely pathogenic and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 26, 2021	The NM_000152.5:c.953T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 318 (p.Met318Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was found in compound heterozygosity (phase unknown) with a unique pathogenic variant in GAA in one patient with Pompe disease (PMID: 21484825). Additional cases (PMID: 18425781) have been reported but were not included because a second variant and/or zygosity was not specified (PP4_Moderate, PM3_Supporting). Expression of the variant in COS cells resulted in 3.2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.926 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: 558700; 1 star review status) with 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652892, 29181627, 19862843, 29122469). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect GAA protein function (PMID: 22644586). This variant has been observed in combination with another GAA variant in  an individual affected with glycogen storage disease (PMID: 21484825). ClinVar contains an entry for this variant (Variation ID: 558700). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 318 of the GAA protein (p.Met318Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.94	P;P
Vest4		0.95
MutPred		0.87		Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.98
gMVP		0.96

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;