ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788013 SCV000927045 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.735A>C (p.Leu245Phe) variant in BRAF has been reported as a a de novo occurrence, one of which was confirmed in at least 4 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx University Magdeburg GTR Lab ID's 21766, 26957, 506381; ClinVar SCV000061622.5, SCV000057188.16 PMID 19416762). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). 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). 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): PS2_VeryStrong, PM2, PM1, PP2, PP3, PS4_Supporting.
GeneDx RCV000033283 SCV000057188 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The L245F variant has been published previously in association with Noonan spectrum disorders, including as an apparently de novo occurrence (Koudova et al., 2009; Sarkozy et al., 2009). It has also been confirmed to occur de novo in an individual sent to GeneDx for testing. The variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different nucleotide change leading to the same missense variant (c.735 A>T) as well as missense variants in nearby residues (T241P/R/M, T244P, A246P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider the variant to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037956 SCV000061622 likely pathogenic Cardio-facio-cutaneous syndrome 2010-06-24 criteria provided, single submitter clinical testing
Invitae RCV000469440 SCV000553831 pathogenic Rasopathy 2019-12-31 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 missense change and a different variant (c.735A>T) giving rise to the same protein effect observed here (p.Leu245Phe) have been observed in individuals affected with BRAF-related conditions (PMID: 19206169, 22190897, 30290804), including one individual in whom the variant was de novo (PMID: 19416762). ClinVar contains an entry for this variant (Variation ID: 40347). 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515291 SCV000611176 likely pathogenic Cardiofaciocutaneous syndrome 1; Lung carcinoma; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037956 SCV001467792 pathogenic Cardio-facio-cutaneous syndrome 2020-12-28 criteria provided, single submitter clinical testing Variant summary: BRAF c.735A>C (p.Leu245Phe) results in a non-conservative amino acid change located in the phorbol ester/diacylglycerol-binding domain (IPR002219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250260 control chromosomes (gnomAD). c.735A>C has been reported in the literature as a de novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome and related phenotypes belonging to the RASopathy spectrum (Koudova_2009, Pekeles_2019, Chinton_2019). In addition, a different variant resulting in the same missense change (c.735A>T (p.Leu245Phe)) has been reported in affected individuals (HGMD). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (3x, including the expert panel) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000171142 SCV000223706 pathogenic LEOPARD syndrome 3 2009-09-01 no assertion criteria provided literature only

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