ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1111T>C (p.Tyr371His) (rs267606706)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441724 SCV000518987 pathogenic not provided 2020-07-29 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Niemeyer et al., 2010; Javadi et al., 2013).; This variant is associated with the following publications: (PMID: 20543203, 25952305, 27609087, 25283271, 19571318, 20694012, 23696637, 24803665, 27577878, 26911351, 28082680, 26676746, 28414188, 32933826)
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
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001527385 SCV001738403 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 2019-12-30 criteria provided, single submitter clinical testing [ACMG/AMP: PS2, PS3, PM1, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is predicted to be damaging by multiple functional prediction tools [PP3].
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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