rs112025212

Variant names:

• chr17-80107863-C-G
• rs112025212
• NM_000152.5:c.922C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80107863-C-G
• chr17-80107863-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000152.5(GAA):​c.922C>G​(p.His308Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,390 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. H308Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.74

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a strand (size 5) in uniprot entity LYAG_HUMAN there are 17 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 chr17-80107864-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1493530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset, glycogen storage disease due to acid maltase deficiency, infantile onset.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-80107863-C-G is Pathogenic according to our data. Variant chr17-80107863-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2140918.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.922C>G	p.His308Asp	missense_variant	Exon 5 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.922C>G	p.His308Asp	missense_variant	Exon 5 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459390 Hom.: 0 Cov.: 52 AF XY: 0.00000138 AC XY: 1 AN XY: 725998

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33442

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44610

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26104

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39652

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86154

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52112

Gnomad4 NFE exome AF: 9.00e-7 AC: 1 AN: 1111698

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1

May 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.His308 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14695532, 19862843, 28624228, 31086307). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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. This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 308 of the GAA protein (p.His308Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.97	D;D
Vest4		0.96
MutPred		0.83		Loss of catalytic residue at G309 (P = 0.1013);Loss of catalytic residue at G309 (P = 0.1013);
MVP		1.0
MPC		0.61
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.97

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: rs112025212; hg19: chr17-78081662;