ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.722C>A (p.Thr241Lys) (rs387906660)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000807047 SCV000947075 uncertain significance Rasopathy 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 241 of the BRAF protein (p.Thr241Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of RASopathy spectrum disorders (Invitae). ClinVar contains an entry for this variant (Variation ID: 44829). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr241 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 17704260, 18042262, 28404629, 19206169), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037953 SCV000061619 pathogenic Noonan syndrome 2013-06-07 criteria provided, single submitter clinical testing The Thr241Lys variant has not been reported in the literature nor been identifie d in our laboratory in over 1,400 individuals. However, two nucleotide variants at this same position (722C>T, Thr241Met; 722C>G, Thr241Arg) have been previousl y reported in two patients with Noonan syndrome (Sarkozy 2009), one of which was shown to have occurred de novo. Moreover, an adjacent variant affecting the sam e amino acid codon (721A>C, Thr241Pro) has been identified in four patients with Cardio-facio-cutaneous syndrome or LEOPARD syndrome (Nava 2007, Schulz 2008, Sa rkozy 2009), with three of these patients having had the variant occur de novo. In addition, this variant was not identified in the parents of this proband. The se data suggest the threonine (Thr) at position 241, and residing within the con served region 1 (CR1) of BRAF, is a functionally important residue and is strong ly associated with Noonan Spectrum disorders. In summary, given the de novo occu rrence, the Thr241Lys variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

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