Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.5(GAA):c.1194+3G>C

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA247031

198393 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4d1ae9e6-ee32-4e9d-b802-71c188a8ca78

Approved on: 2024-05-21

Published on: 2024-10-25

HGVS expressions

NM_000152.5:c.1194+3G>C

NM_000152.5(GAA):c.1194+3G>C

NC_000017.11:g.80108610G>C

CM000679.2:g.80108610G>C

NC_000017.10:g.78082409G>C

CM000679.1:g.78082409G>C

NC_000017.9:g.75697004G>C

NG_009822.1:g.12055G>C

ENST00000570803.6:c.1194+3G>C

ENST00000572080.2:c.1194+3G>C

ENST00000577106.6:c.1194+3G>C

ENST00000302262.8:c.1194+3G>C

ENST00000302262.7:c.1194+3G>C

ENST00000390015.7:c.1194+3G>C

NM_000152.3:c.1194+3G>C

NM_001079803.1:c.1194+3G>C

NM_001079804.1:c.1194+3G>C

NM_000152.4:c.1194+3G>C

NM_001079803.2:c.1194+3G>C

NM_001079804.2:c.1194+3G>C

NM_001079803.3:c.1194+3G>C

NM_001079804.3:c.1194+3G>C

Uncertain Significance

PP4_Moderate PM2_Supporting PM3

PP3

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1194+3G>C variant in GAA is located in the donor splice site consensus region of intron 7. The variant has been identified in four individuals, three with documented laboratory values showing GAA activity in the affected range in dried blood spots (Clinical Diagnostic Laboratories, PMID: 33073003). One of these individuals is reported to be symptomatic, with GAA activity in the affected range in dried blood spots, and absence of known pseudodeficiency variants (PP4_Moderate); this individual is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP - c.1210G>A (p.Asp404Asn), ClinVar Variation ID: 657348, SCV002817441.1, confirmed in trans (Clinical Laboratory) (PM3). The other individuals were identified on newborn screen will not be included because it is unknown if they are clinically symptomatic or if the enzyme deficiency could be the result of pseudodeficiency. These individuals are compound heterozygous for the variant and either c.1781G>A (p.Arg594His) (in trans based on testing of one parent), ClinVar Variation ID: 972747; SCV002817431.1; c.1841C>A (p.Thr614Lys), ClinVar Variation ID: 167113, SCV001371751.1, phase unknown (Clinical Laboratory); or c.1827del (ClinVar Variation ID: 188936, SCV001371738.1) (Clinical Laboratory). The highest population minor allele frequency in gnomAD v2.1.1. is 0.0003149 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.17 for loss of the intron 7 donor splice site, and a score of 0.31 for loss of the intron 6 acceptor splice site suggesting possible effect on splicing but not meeting the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP (PP3 not met). There is a ClinVar entry for this variant (Variation ID: 198393). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024)

PP4_Moderate

The variant has been identified in four individuals, three with documented laboratory values showing deficient GAA activity (Clinical Diagnostic Laboratories, PMID: 33073003). Three individuals were identified on newborn screen and no further clinical information, regarding presence of symptoms, is available. The fourth patient is reported to be symptomatic, with GAA activity in the affected range in dried blood spot, and known pseudodeficiency variants are absent (PP4_Moderate).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1. is 0.0003149 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In gnomAD v4.1 the MAF is 0.0003187 (376/1179920 alleles) in the European non-Finnish population, also meeting PM2_Supporting.

PM3

One individual, reported to be affected with Pompe disease, is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP - c.1210G>A (p.Asp404Asn), ClinVar Variation ID: 657348, SCV002817441.1, confirmed in trans, 1 point (Clinical Laboratory). Data from the three individuals identified on newborn screen will not be included because it is unknown if they are clinically symptomatic. These individuals are compound heterozygous for the variant and either c.1781G>A (p.Arg594His) (in trans based on testing of one parent), ClinVar Variation ID: 972747; SCV002817431.1, or c.1841C>A (p.Thr614Lys), ClinVar Variation ID: 167113, SCV001371751.1, phase unknown, or c.1827del (ClinVar Variation ID: 188936, SCV001371738.1) (Clinical Laboratory). Total 1 point, PM3.

PP3

The NM_000152.5:c.1194+3G>C variant in GAA is located in the donor splice site consensus region of intron 7. The computational predictor SpliceAI gives a score of 0.17 for loss of the intron 7 donor splice site, and a score of 0.31 for loss of the intron 6 acceptor splice site suggesting possible effect on splicing but not meeting the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP (PP3 not met).

Curation History

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