rs914396317

Variant names:

• chr17-80112680-C-G
• rs914396317
• NM_000152.5:c.1857C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80112680-C-G
• chr17-80112680-C-T

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PS3_Supporting PP3 PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369658/MONDO:0009290/010

• 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:5
• 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 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1857C>G	p.Ser619Arg	missense_variant	Exon 13 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1857C>G	p.Ser619Arg	missense_variant	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3

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:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Jan 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14643388, 25213570, 27363342). ClinVar contains an entry for this variant (Variation ID: 550825). 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: 14643388, 21471980). 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. For these reasons, this variant has been classified as Pathogenic. -

Feb 24, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

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
LIST_S2	Uncertain	0.89	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H
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;