rs200412003

chr17-80108382-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP3_Strong PP5_Strong

The NM_000152.5(GAA):c.1048G>A(p.Val350Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V350A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:10
• Conservation: PhyloP100: 9.38

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 17-80108382-G-A is Pathogenic according to our data. Variant chr17-80108382-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 555998.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=9, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1048G>A	p.Val350Met	missense_variant	6/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1048G>A	p.Val350Met	missense_variant	6/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000956 AC: 24 AN: 251022 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135858

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461186 Hom.: 0 Cov.: 38 AF XY: 0.0000949 AC XY: 69 AN XY: 726902

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000550

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2 Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000152.3(GAA):c.1048G>A(V350M) is a missense variant classified as a variant of uncertain significance in the context of Pompe disease. V350M has been observed in cases with relevant disease (PMID 25451853, 23430949). Functional assessments of this variant are not available in the literature. V350M has been observed in population frequency databases (gnomAD: FIN 0.05%). In summary, there is insufficient evidence to classify NM_000152.3(GAA):c.1048G>A(V350M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 19, 2024	The NM_000152.5(GAA):c.1048G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 350 (p.Val350Met). This variant has been detected in at least 12 individuals, and at least 11 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (Clinical Laboratory data, PMIDs: 25451853, 36310651, 36246652). However, in the absence of clinical symptoms to support that the variant causes Pompe disease, PP4 was not applied. Of those individuals, 1 was homozygous for the variant, and 11 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant in GAA; 2 of those were confirmed in trans by parental testing, including c.-32-13T>G (9 patients, Clinical laboratory data, PMID:25451853, 1 patient confirmed in trans), c.2051C>T (p.Pro684Leu) (1 patient, PMID:36310651, phase unknown), c.1589del (p.Glu530GlyfsTer48) (1 patient, PMID: 36246652, phase unknown), and c.2238G>C (p.Trp746Cys) (2 patients, one confirmed in trans and one with a pseudodeficiency allele, Clinical Laboratory data). Due to lack of clinical symptoms in these patients, PM3 is not met at the current time. When expressed in HEK293 cells, GAA enzyme activity was 1.5% of the positive control (Table 3). Western blot revealed faint precursor (110 k Da) and mature (76 kDa) protein bands with lower intensity compared to the positive control, indicating this variant may be impacting GAA protein stability and processing (PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00013 (17/1128822 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.878 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: 555998). In summary, while patients with this variant have been reported with deficiency GAA activity, and the variant has been found in compound heterozygosity with pathogenic and likely pathogenic variants in GAA, the Lysosomal Diseases VCEP concluded that there is insufficient phenotypic evidence to indicate that this variant cuases Pompe disease at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val350Met variant in GAA has been reported in 2 individuals with glycogen storage disease II (PMID: 25786784, 25451853) and has been identified in 0.04% (11/25122) of European (Finnish) chromosomes, 0.013% (17/128822) of European (non-Finnish) chromosomes, and 0.004% (1/24900) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200412003). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Counsyl and Invitae (VariationID: 555998). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle and lymphocytes being <10% of wild type, consistent with disease (PMID: 25786784, 25451853). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G and in individuals with glycogen storage disease II slightly increases the likelihood that the p.Val350Met variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PM2, PP3, PP4 (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 350 of the GAA protein (p.Val350Met). This variant is present in population databases (rs200412003, gnomAD 0.05%). This missense change has been observed in individual(s) with Pompe disease (PMID: 23430949, 25451853, 36246652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 36246652). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	GAA: PM2, PM3, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	Reported previously as heterozygous along with another variant in the GAA gene in an asymptomatic adult with decreased alpha glucosidase activity in multiple tissues (Echaniz-Laguna et al., 2015); 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: 23430949, 25786784, 24627108, 25451853) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 24, 2022

Variant summary: GAA c.1048G>A (p.Val350Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251022 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (9.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.1048G>A has been reported in the literature as heterozygous occurrence, along with a known pathogenic variant, in individual(s) with asymptomatic Pompe disease/Pompe disease presenting with a pure vascular phenotype, and with decreased alpha glucosidase activity in different tissues (Echaniz-Laguna_2015, Quenardelle_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MVP		0.95
MPC		0.54
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200412003; hg19: chr17-78082181;