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]

Link to SEPIO compliant JSON-LD document

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

CA247031

198393 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

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

Likely Pathogenic

PM3_Strong PP4_Moderate PM2_Supporting

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

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 three patients, all with documented laboratory values showing deficient GAA activity (Clinical Diagnostic Laboratories, PMID: 33073003) (PP4_Moderate). All of these patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP, including c.1781G>A (p.Arg594His), LP (mother is heterozygous for c.1781G>A, no paternal testing), (Clinical Laboratory, PMID: 33073003); c.1210G>A (p.Asp404Asn), confirmed in trans (Clinical Laboratory), and c.1841C>A (p.Thr614Lys), phase unknown,(Clinical Laboratory (PM3_Strong). The computational predictor SpliceAI does not predict a strong impact on splicing (all scores<0.2). However, varSEAK classifies that variant as having a splicing effect (class 5). There is a ClinVar entry for this variant (Variation ID: 198393). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 6, 2022)

PM3_Strong

Three patients have been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP, including c.1781G>A (p.Arg594His), LP (mother is heterozygous for c.1781G>A, no paternal testing), 0.5 points (Clinical Laboratory, PMID: 33073003); c.1210G>A (p.Asp404Asn), confirmed in trans, 1 point (Clinical Laboratory), and c.1841C>A (p.Thr614Lys), phase unknown, 0.5 points (Clinical Laboratory. Total 2 points (PM3_Strong).

PP4_Moderate

The variant has been identified in three patients, all with documented laboratory values showing deficient GAA activity (Clinical Diagnostic Laboratories, PMID: 33073003) (PP4_Moderate).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00031 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PP3

The computational predictor SpliceAI does not predict a strong impact on splicing (all scores<0.2). However, varSEAK classifies that variant as having a splicing effect (class 5).

Approved on: 2022-12-06

Published on: 2022-12-20

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