ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.735A>T (p.Leu245Phe) (rs397507466)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788012 SCV000927044 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.735A>T p.Leu245Phe variant in BRAF has been identified in at least 2 independent occurrences, one of which was de novo, in patients with clinical features of a RASopathy (PM6, PS4_Supporting; Partners LMM, University Magdeburg internal data; GTR Lab IDs: 21766, 506381 PMID: 19206169, 22190897). This variant was absent from large population studies (PM2; gnomAD, Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). 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). Of note, the p.Leu245Phe change has also been reported as a consequence of the c.735A>C variant in BRAF, which has been classified as pathogenic and therefore supports that this residue may be critical to protein function (PS1; ClinVar ID: 40347). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). 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): PS4_Supporting, PM6, PM1, PM2, PS1, PP2, PP3.
GeneDx RCV000033284 SCV000057189 pathogenic not provided 2012-03-28 criteria provided, single submitter clinical testing The L245F missense mutation in the BRAF gene has been published previously in association with Cardio-Facio-Cutaneous (CFC) Syndrome (Sarkozy et al., 2009). It has also been reported in an individual with LEOPARD syndrome and normal intelligence (Koudova et al., 2009). L245F results in a non-conservative amino acid substitution in that a small, compact Leucine residue is replaced with a large, bulky Phenylalanine at a position that is highly conserved. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037957 SCV000061623 likely pathogenic Cardio-facio-cutaneous syndrome 2012-08-22 criteria provided, single submitter clinical testing The Leu245Phe variant in BRAF has been previously identified in the literature i n two patients, one with clinical features of Cardio-Facio-Cutaneous Syndrome an d one with clinical features of Leopard Syndrome, and was shown to be absent fro m 600 control chromosomes (Sarkozy 2009, Koudova 2009). This variant has been pr eviously identified by our laboratory in a single patient with clinical features of Noonan Syndrome but the nucleotide change differs (c.735A>C). In one patient , the variant was shown to have occured de novo (Koudova 2009). Moreover, this v ariant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project ( Computational analyses ( biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summa ry, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
Invitae RCV000688777 SCV000816401 likely pathogenic Rasopathy 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 245 of the BRAF protein (p.Leu245Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cardio-facio-cutaneous syndrome (PMID: 19206169, 22190897). ClinVar contains an entry for this variant (Variation ID: 40348). 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: "Probably Damaging"; Align-GVGD: "Class C0"). A different variant (c.735A>C) giving rise to the same protein effect observed here (p.Leu245Phe) has been reported in an individual affected with cardio-facio-cutaneous syndrome (PMID: 19416762), indicating that this residue may be critical for protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews RCV000055897 SCV000086905 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.

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