rs374470794

Variant names:

• chr17-80112625-C-A
• rs374470794
• NM_000152.5:c.1802C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80112625-C-A
• chr17-80112625-C-G
• chr17-80112625-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP4 PM3_Supporting PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.1802C>A (p.Ser601Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that a patient with this variant has no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 21687968). The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with c.525del in one patient with Pompe disease meeting the specifications for PP4. The phase is unknown (PMID 26497565). This data meets PM3_Supporting. A patient with the same genotype has been reported (PMID 21687968) and might be the same patient but this could not be verified. There is a ClinVar entry for this variant (Variation ID: 593486, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Suporting, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369436/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.75
• Publications: 29 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: 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.
• 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.1802C>A	p.Ser601*	stop_gained	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.1802C>A	p.Ser601*	stop_gained	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460668 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726684

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60372

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:2

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser601*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with GAA-related conditions (PMID: 21687968, 29422078). ClinVar contains an entry for this variant (Variation ID: 593486). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Jun 03, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.1802C>A (p.Ser601Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that a patient with this variant has no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 21687968). The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with c.525del in one patient with Pompe disease meeting the specifications for PP4. The phase is unknown (PMID 26497565). This data meets PM3_Supporting. A patient with the same genotype has been reported (PMID 21687968) and might be the same patient but this could not be verified. There is a ClinVar entry for this variant (Variation ID: 593486, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Suporting, PM2, PP4. -

not provided Pathogenic:2

Jul 31, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
Vest4		0.97
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: 2

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

Other links and lift over

dbSNP: rs374470794; hg19: chr17-78086424;