ClinVar

Description

This variant, c.2161del (p.Glu721ArgfsTer?), is a frameshift variant predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was identified by a clinical diagnostic laboratory in a compound heterozygous individual with c.841C>T (p.Arg281Trp). Pseudodeficiency variants are absent in this individual, allowing PP4_Moderate to be applied. The in trans data from this patient was used in the classification of p.Arg281Trp and is not included here in order to avoid a circular argument. An additional case has been reported with p.Glu721ArgfsTer (cDNA sequence not provided), identified by newborn screening and compound heterozygous for p.Trp746Leu and the psuedodeficiency variant p.Asp91Asn (PMIDs 28196920, 29095812). There is no ClinVar entry for this variant and, to our knowledge, functional studies are unavailable. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4_Moderate.