Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
A single heterozygous SOS1 missense variant (c.472A>G (p.Thr158Ala)) was identified in an individual presenting with overlapping Costello and cardio-facio-cutaneous phenotypes, consistent with autosomal dominant inheritance and a de novo event without reported segregation (PMID:23528009). This represents the only documented SOS1 alteration in Costello syndrome to date, yielding limited genetic evidence for causality.
Functional assays in 293T cells demonstrated that the p.Thr158Ala substitution disrupts the autoinhibitory histone-fold domain, leading to premature and amplified ERK1/2 phosphorylation kinetics (peak at 5 min vs. 15 min in wild-type) and altered PI3K/AKT pathway modulation, consistent with a gain-of-function mechanism in RAS/MAPK signaling (PMID:23528009). These data provide moderate experimental support but warrant further replication in clinical cohorts to establish definitive disease association.
Key Take-home: Screening of SOS1 in Costello-like presentations may uncover rare gain-of-function alleles, although broader case series and segregation studies are required to validate clinical utility.
Gene–Disease AssociationLimitedSingle unrelated proband with SOS1 variant in Costello syndrome; no segregation data Genetic EvidenceLimitedOne missense variant (c.472A>G) identified in a patient with Costello/CFC phenotype; absence of familial segregation Functional EvidenceModerateIn vitro transfection assays demonstrate altered RAS/MAPK and PI3K/AKT signaling (gain-of-function) |