PPP1CB was first reported in relation to autosomal dominant Noonan syndrome with loose anagen hair (AD NS-LAH) as early as 2016 (Gripp et al., PMID: 27264673). At least 4 unique missense variants (including the recurrent de novo p.Pro49Arg variant) have been reported in humans with this disorder. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 5 publications (PMID: 25356899, 27264673, 27681385, 27868344, 28211982). More evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 30236064). The mechanism of disease is thought to result in more stable/prolonged binding of SHOC2 and PPP1C to MRAS, which is expected to promote a more effective/prolonged RAF p.Ser259 dephosphorylation (PMID: 26446362, 23875798, 16630891). This gene-disease association is supported by relevant experimental evidence implicating a physical association of PP1c (of which PPP1CB is a subunit) with SHOC2, which is definitively associated with NS-LAH (PMID: 16630891, 24211266). The ClinGen RASopathy Expert Panel has assessed PPP1CB for associations with Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. In summary, PPP1CB is definitively associated with AD NS-LAH. This curation was approved by the ClinGen RASopathy Expert Panel on 4/23/20 (SOP Version 7).
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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