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_001079804.3:c.1400T>C

CA401366522

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 349e0b82-6338-4b3a-a5da-e902a32952d0

Approved on: 2024-01-16

Published on: 2024-03-26

HGVS expressions

NM_001079804.3:c.1400T>C

NC_000017.11:g.80110018T>C

CM000679.2:g.80110018T>C

NC_000017.10:g.78083817T>C

CM000679.1:g.78083817T>C

NC_000017.9:g.75698412T>C

NG_009822.1:g.13463T>C

ENST00000570803.6:c.1400T>C

ENST00000572080.2:c.1400T>C

ENST00000577106.6:c.1400T>C

ENST00000302262.8:c.1400T>C

ENST00000302262.7:c.1400T>C

ENST00000390015.7:c.1400T>C

NM_000152.3:c.1400T>C

NM_001079803.1:c.1400T>C

NM_001079804.1:c.1400T>C

NM_000152.4:c.1400T>C

NM_001079803.2:c.1400T>C

NM_001079804.2:c.1400T>C

NM_000152.5:c.1400T>C

NM_001079803.3:c.1400T>C

Likely Pathogenic

PP3 PM3 PM2_Supporting PP4_Moderate

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5: c.1400T>C variant in GAA is predicted to result in the missense substitution of phenylalanine by serine at amino acid 467 (p.Phe467Ser). This variant has been detected in one patient with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and on enzyme replacement therapy (Clinical Diagnostic Laboratory) (PP4_Moderate). This variant was confirmed to be in trans with c.2560C>T (p.Arg854Ter), a GAA variant classified as pathogenic by the ClinGen LD VCEP (ClinVar Variation ID: 4034, SCV001371731.1), in one patient with IOPD (Clinical Diagnostic Laboratory) (PM3). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational meta-predictor REVEL has a score of 0.941 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). 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 LD VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP on Jan 16, 2024).

PP3

The computational meta-predictor REVEL has a score of 0.941 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3).

PM3

This variant was confirmed (both parents being tested) to be in trans with c.2560C>T (p.Arg854Ter), a GAA variant classified as pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (ClinVar Variation ID: 4034, SCV001371731.1), in one patient with IOPD (Clinical Diagnostic Laboratory) (1.0 point; PM3).

PM2_Supporting

Absent in gnomAD v2.1.1. and v4.0 (PM2_Supporting).

PP4_Moderate

This variant has been detected in one patient with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and on enzyme replacement therapy (ERT) (Clinical Diagnostic Laboratory) (2 points; PP4_Moderate). The patient has biventricular concentric cardiac hypertrophy, positive newborn screen, abnormal urine Hex4 and positive CRIM status.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.