P695: Uncertainty in interpretation of GAA variants detected through newborn screening without clinical manifestation of Pompe disease

Pompe disease is an autosomal recessive lysosomal disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase encoded by GAA. Pompe disease exhibits a broad phenotypic spectrum with considerable variability in disease natural history and symptoms. Classical infantile onset Pompe disease (IOPD) is characterized by cardiomegaly and hypotonia in the first year of life, and if untreated, results in death from respiratory distress. Late onset Pompe disease (LOPD) represents the other end of the spectrum, presenting primarily with muscle weakness with onset anywhere from childhood to late adulthood. The ClinGen Lysosomal Disease Variant Curation Expert Panel (VCEP) has been established to evaluate evidence required to classify GAA variants in accordance to ACMG criteria on a spectrum from pathogenic to benign in patients with Pompe disease. The inclusion of Pompe disease on the recommended universal screening panel (RUSP) for newborn screening (NBS) in 2015 has led to the identification of asymptomatic infants with potential LOPD. The ClinGen Lysosomal Diseases VCEP has found it challenging to classify variants, detected primarily through NBS, that are predicted to be damaging based on current ACMG criteria including deficient enzyme activity on confirmatory biochemical testing, but lack patient phenotype data to support these predictions. We reviewed available data for several variants identified through clinical laboratories and literature searches in patients with positive Pompe NBS, deficient enzyme activity on confirmatory testing, two variants detected through GAA sequencing, but no associated phenotypic features. Here, we will discuss our VCEP’s strategy for classifying these variants by highlighting three pertinent examples, c.726G>A Ala242=, c.1019A>G Tyr340Cys, and c.1048G>A p.Val350Met. This phenomenon could be explained by either the presence of a variant associated with LOPD or associated with “pseudodeficiency” which would not be predicted to cause disease. The absence of case reports of patients with these variants makes their classification challenging, leaving families in a state of uncertainty given the delayed onset of LOPD symptoms. Recognizing the need for specific guidelines addressing variants detected by NBS programs, the Lysosomal Diseased VCEP has adopted a conservative approach in our interpretation of these variants by refraining from classifying variants as likely pathogenic or pathogenic without evidence of phenotypic features. Longitudinal studies tracking these infants over their lifespan will be critical to establish the clinical implications of such variants and addressing the prevailing uncertainty in classification.

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