ClinVar

Description

The GAA c.841C>T variant is predicted to result in the amino acid substitution p.Arg281Trp. This variant has been reported along with a second causative variant in individuals with late-onset Pompe disease (LOPD) or by newborn screening (Ficicioglu et al. 2020. PubMed ID: 33202836; Wencel et al. 2021. PubMed ID: 36299500). This variant was also reported in an individual with LOPD and an individual identified by newborn screening; a second variant was not identified in either individual (Angelini et al. 2012. PubMed ID: 22081099; Wittmann et al. 2012. PubMed ID: 23430949). It was also identified along with a likely benign intronic variant in an individual diagnosed with Pompe disease (Table S3, Kishnani et al. 2019. PubMed ID: 31086307). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from pathogenic to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/283894). The ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel interprets this variant as likely pathogenic and cites internal data from clinical diagnostic laboratories in their interpretation, mentioning the c.841C>T (p.Arg281Trp) variant was found with a second pathogenic variant (c.2481+102_2646+31del or c.2161del) in two individuals, with the variants confirmed to be on opposite alleles (i.e., in trans) in one of the individuals. Based on the collective evidence, we interpret this variant as likely pathogenic.