Submission Details

LZTR1 was associated with autosomal dominant Noonan syndrome by Chen et al. in 2014. Evidence supporting this gene-disease relationship includes case-level data and an animal model. At least 10 unique variants have been reported in humans with Noonan syndrome. In addition to those described in the literature, six variants with confirmed de novo inheritance and one variant with unconfirmed de novo inheritance have been identified at GeneDx in individuals with features consistent with a RASopathy (SCV000330730, SCV000491887, SCV000619636, SCV000778848, SCV000778849, SCV000778850, SCV000568857). Several missense and other non-LOF variants have been identified to segregate in a dominant manner, while heterozygous LOF variants have been found in unaffected carriers in families with recessive Noonan syndrome, therefore, the suspected mechanism of disease in LZTR1 is dominant-negative. Further functional evidence is required to solidify this mechanism (Johnston et al., 2018). In summary, LZTR1 is definitively associated with autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, LZTR1 has also been classified as strong in relation to autosomal recessive Noonan syndrome. Additionally, the ClinGen RASopathy Expert Panel has assessed LZTR1 for associations with both autosomal dominant and recessive forms of Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, and Cardiofaciocutaneous syndrome, but no evidence was reported. This classification was approved by the ClinGen RASopathy Expert Panel on 4/23/2020.