rs914396317

chr17-80112680-C-Gchr17-80112680-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1857C>G(p.Ser619Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,978 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 Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S619N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 2.04

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 22 ACMG points.

• PS1: Transcript NM_000152.5 (GAA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2702493
• PM1: In a hotspot region, there are 7 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 chr17-80112679-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-80112680-C-G is Pathogenic according to our data. Variant chr17-80112680-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 550825.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112680-C-G is described in Lovd as [Pathogenic]. Variant chr17-80112680-C-G is described in Lovd as [Likely_pathogenic]. Variant chr17-80112680-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1857C>G	p.Ser619Arg	missense_variant	13/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1857C>G	p.Ser619Arg	missense_variant	13/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458978 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 725668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2022	The NM_000152.5:c.1857C>G variant in GAA is predicted to result in the substitution of serine by arginine at amino acid 619 (p.Ser619Arg). This variant has been reported in at least 10 patients with features consistent with Pompe disease including individuals with clinical symptoms of Pompe disease and documented laboratory data showing GAA activity below the normal reference range or <10% in relevant tissues (PMID: 14643388, 17092519, 29124014, 21984055, 23884227), and additional patients without GAA activity reported but on enzyme replacement therapy (PMID: 25213570, 29869463) (PP4_Moderate). Five patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.1579_1580del (p.Arg527GlyfsTer3), confirmed in trans (PMID: 29869463); c.1156C>T (p.Gln386Ter), phase unknown (PMID: 23884227); c.1309C>T (p.Arg437Cys), phase unknown (PMID: 29124014); c.1798C>T (p.Arg600Cys), phase unknown (PMID: 29124014); and c.1735G>A (p.Glu579Lys), phase unknown (PMID: 29124014); and at least three are homozygous for the variant (PMID: 14643388, 29124014) (maximum allowed = 2 x 0.5 points = 1 point). Additional patients have been reported who are compound heterozygous for the variant and either c.875A>G (p.Tyr292Cys) (PMID: 23884227, 25213570), or c.2015G>A (p.Arg672Gln) (PMID: 17092519). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Finally, additional patients may also carry the variant but were not included because the cDNA change for the variant was not reported (PMID: 17805474, 18495398, 21676566) (PM3_Very Strong). When expressed in COS cells in two seprate function, studies, the variant results in <2% GAA activity compared to wild type (PMIDs: 14643388, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.795 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 550825). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2023	Experimental studies have shown that this missense change affects GAA function (PMID: 14643388, 21471980). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16838077, 24158270, 25998610). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 550825). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14643388, 25213570, 27363342). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 619 of the GAA protein (p.Ser619Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.96		Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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: rs914396317; hg19: chr17-78086479;