The c.27dup (p.Gln10fs) variant in LZTR1 is a frameshift variant predicted to cause a premature stop codon 24 amino acids downstream in biologically-relevant-exon 1 (of 21) and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001139 (4/13466 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 individual with RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and which was confirmed in trans by family testing (c.1943-256C>T (p.T648fs*36), 1 PM3 point, PMID: 32623905) (PM3). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK supporting the abnormal impact due to loss of LZTR1 function (PMID:32623905)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PS3_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024)