17-80117724-G-C

Variant names:

• chr17-80117724-G-C
• rs374687883
• NM_000152.5:c.2456G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PS3_Moderate PM2_Supporting PM3 PM5_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID:22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID:30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401325305/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.08
• Publications: 1 publications found

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]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.
• PM5: 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.2456G>C	p.Arg819Pro	missense_variant	Exon 17 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2456G>C	p.Arg819Pro	missense_variant	Exon 17 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458892 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725656

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Jun 30, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID: 30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting. -

Apr 11, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.2456G>C (p.Arg819Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 31, C-terminal domain (IPR048395) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242628 control chromosomes. c.2456G>C has been reported in the literature in several individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; e.g. Bali_2012, Kazi_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Kroos_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22252923, 22644586, 30214072). ClinVar contains an entry for this variant (Variation ID: 1693550). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 28, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		9.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.77		Loss of methylation at R819 (P = 0.0222);Loss of methylation at R819 (P = 0.0222);
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374687883; hg19: chr17-78091523;