17-80108724-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000152.5(GAA):c.1222A>G(p.Met408Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,460,294 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M408T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 2.56

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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr17-80108725-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2879868.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 17-80108724-A-G is Pathogenic according to our data. Variant chr17-80108724-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371235.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80108724-A-G is described in Lovd as [Pathogenic]. Variant chr17-80108724-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1222A>G	p.Met408Val	missense_variant	8/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1222A>G	p.Met408Val	missense_variant	8/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248202 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134944

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460294 Hom.: 0 Cov.: 36 AF XY: 0.0000206 AC XY: 15 AN XY: 726438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 06, 2020	This variant, 1222A>G, (p.Met408Val), is a missense substitution which has been reported in two individuals with infantile onset Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. One of these patients is homozygous for the variant (PMID 26497565). The other patient is compound heterozygous for the variant and c.1408_1410del (p.Asn470del) (PMID 11738358); however, this in trans data was used in the assessment of p.Asn470del, and will not be used here in order to avoid circular logic. Based on this data, PM3_Supporting is met. When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843), meeting PS3. The score for the REVEL in silico predictor, 0.637, meets neither PP3 nor BP4. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied: PS3, PM2, PM3_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2019	Variant summary: GAA c.1222A>G (p.Met408Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248202 control chromosomes (gnomAD). c.1222A>G has been reported in the literature in homozygous or compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Fernandez-Hojas_2002, Gort_2007, Labrousse_2010, Manwaring_2012, Broomfield_2016). These data indicate that the variant is likely to be associated with disease. The variant protein was reported to have less than 2% GAA activity in an in vitro expression system (Flanagan_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2023	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 408 of the GAA protein (p.Met408Val). This variant is present in population databases (rs560575383, gnomAD 0.002%). This missense change has been observed in individual(s) with Pompe disease (PMID: 11738358, 21687968). ClinVar contains an entry for this variant (Variation ID: 371235). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 29, 2022	The GAA c.1222A>G variant is classified as Likely Pathogenic (PM2_Supporting, PS3, PM3-supporting, PP4_Moderate) The GAA c.1222A>G variant is a single nucleotide change in exon 8/20 of the GAA gene, which is predicted to change the amino acid methionine at position 408 in the protein to valine. This variant is absent from population databases (PM2_supporting). Functional studies show that the variant results in less than 2% of wild-type GAA activity (PMID:19862843) (PS3). This variant has been detected as homozygous and compound heterozygous in affected patients (PMID:26497565, 11738358) (PM3_supporting). The clinical features of this case are highly specific for a variant in the GAA gene (PP4_moderate). The variant has been reported in dbSNP (rs560575383) and in the HGMD database (CM020004). It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 371235). -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Met408Val variant in GAA has been reported in 5 individuals (including 2 Spanish, 2 from the UK, and 1 Taiwanese) with Glycogen Storage Disease II (PMID: 11738358, 21687968, 17616415, 26497565, 20080426), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 371235). This variant has been identified in 0.002% (2/111716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs560575383). 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 COS cells transfected with this variant provide some evidence that the p.Met408Val variant may impact GAA activity (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Methionine (Met) at position 408 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Met408Val variant is pathogenic (PMID: 26497565). The phenotype of an individual homozygous and 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormal GAA activity assay results in relevant tissues (PMID: 26497565, 17616415, 11738358). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP4, PM3_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.71	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;D
Vest4		0.63
MVP		0.99
MPC		0.52
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs560575383; hg19: chr17-78082523;