ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.730A>C (p.Thr244Pro) (rs397507465)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000037955 SCV000616358 pathogenic Cardio-facio-cutaneous syndrome 2017-04-03 reviewed by expert panel curation The c.730A>C (p.Thr244Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 17551924 and 18042262). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr244Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS2.
GeneDx RCV000033282 SCV000057187 pathogenic not provided 2017-12-12 criteria provided, single submitter clinical testing The T244P variant in the BRAF gene has previously been reported in multiple individuals with disorders in the Noonan syndrome spectrum (Gripp et al., 2007; Schulz et al., 2008; van Trier et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016). The T244P 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. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Missense variants in nearby residues (T241P, T241M, A246P) have been reported in association with disorders in the Noonan syndrome spectrum, supporting the functional importance of this region of the protein (Niihori et al., 2006; Nava et al., 2007; Sarkozy et al., 2009). Furthermore, the majority if missense variants in this gene are considered pathogenic (Stenson et al., 2014). Based on the currently available information, we consider T244P to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037955 SCV000061621 pathogenic Cardio-facio-cutaneous syndrome 2014-11-19 criteria provided, single submitter clinical testing The p.Thr244Pro variant in BRAF has been reported in the literature and our labo ratory in 6 individuals with RASopathies, three of which occurred de novo (Gripp 2007, Schulz 2008, LMM unpublished data). It was absent from large population s tudies. In summary, this variant meets our criteria to be classified as pathogen ic for RASopathies in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon de novo occurences and absence from controls.
Invitae RCV000804367 SCV000944273 pathogenic Rasopathy 2018-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 244 of the BRAF protein (p.Thr244Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of the RASopathies spectrum. This variant occurred de novo in two of these affected individuals (PMID: 17551924, 27521173, 18042262). ClinVar contains an entry for this variant (Variation ID: 40346). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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