LZTR1 was first reported in relation to autosomal recessive Noonan syndrome in 2018 (Johnston et al., PMID: 29469822). The split curation for autosomal dominant Noonan syndrome has been curated separately. 27 variants (missense, nonsense, frameshift, and splicing) that have been reported in 18 probands in 4 publications (PMIDs: 29469822, 29959388, 30859559, 31182298) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by interaction between LZTR1 and the RAF1/SHOC2/PPP1CB complex (PMIDs: 30368668). In summary, there is definitive evidence supporting the relationship between LZTR1 and autosomal recessive 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 definitive in relation to autosomal dominant 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 gene-disease pair was originally evaluated by the RASopathy GCEP on July 24, 2018. It was re-evaluated on August 27, 2020 (SOP Version 9). As a result of this reevaluation, the classification increased from Limited to Definitive with the addition of additional published cases (PMIDs: 29959388, 30859559, 31182298) and experimental evidence (PMID: 30368668).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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