ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.1111T>C (p.Tyr371His) (rs267606706)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441724 SCV000518987 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The Y371H variant in the CBL gene has been reported previously in individuals with JMML and Noonan-like syndrome (Loh et al., 2009; Perez et al., 2010; Martinelli et al., 2015; Hyakuna et al., 2015). The Y371H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y371H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs in the linker domain at a position that is well-conserved across species (Martinelli et al, 2010). Codon 371 appears to be a hot spot for pathogenic variants associated with a Noonan-like phenotype and predisposition to juvenile myelomonocytic leukemia, as multiple missense variants at this same residue (Y371D, Y371N, Y371C) have been reported in the Human Gene Mutation Database (Stenson et al., 2014). One functional study showed Y371H induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 in hematopoietic cells (Niemeyer et al., 2010). Another functional study demonstrated expression of CBL Y371H in a human hematopoietic cell line resulted in elevated JAK2 and LYN kinase, enhanced S6 phosphorylation, and increased cell survival compared to wild-type cells (Javadi et al., 2013). Therefore, we interpret Y371H as a pathogenic variant.
Invitae RCV000691502 SCV000819285 pathogenic Rasopathy 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 371 of the CBL protein (p.Tyr371His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs267606706, ExAC 0.01%). This variant has been reported in multiple individuals affected with juvenile myelomonocytic leukemia and Noonan-like syndrome, including several individuals in which the germline variant was found to be de novo (PMID: 20543203, 20694012, 25283271, 25952305, 28414188). ClinVar contains an entry for this variant (Variation ID: 13811). Experimental studies have shown that this missense change results in cytokine-independent cell proliferation, constitutive phosphorylation of ERK, AKT and S6, increased expression levels of JAK2 and LYN kinases, and diminished E3 ligase activity (PMID: 20694012, 23696637). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000441724 SCV000927151 pathogenic not provided 2017-02-14 criteria provided, single submitter clinical testing
OMIM RCV000014822 SCV000035077 pathogenic Noonan syndrome-like disorder with juvenile myelomonocytic leukemia 2010-10-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437548 SCV000505199 likely pathogenic Hematologic neoplasm 2014-12-26 no assertion criteria provided literature only

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