ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.2034T>G (p.Asp678Glu) (rs180177042)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150199 SCV000197128 pathogenic Cardio-facio-cutaneous syndrome 2013-08-27 criteria provided, single submitter clinical testing The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic ( based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence.
GeneDx RCV000157831 SCV000207761 pathogenic not provided 2017-12-24 criteria provided, single submitter clinical testing The D638E variant in the BRAF gene has been reported previously as a de novo variant in individuals with BRAF-related disorders (Sarkozy et al., 2009; Kleefstra et al., 2011; Sajan et al., 2017). The D638E variant is not observed in large population cohorts (Lek et al., 2016). The D638E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret D638E as a pathogenic variant.
Ambry Genetics RCV000624589 SCV000742118 pathogenic Inborn genetic diseases 2017-01-05 criteria provided, single submitter clinical testing
Invitae RCV000689333 SCV000816979 pathogenic Rasopathy 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 638 of the BRAF protein (p.Asp638Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with cardio-facio-cutaneous syndrome (CFC) and Costello syndrome and has been observed to be de novo in individuals affected with CFC (PMID: 16804887,18039235, 22495831, 16804887). ClinVar contains an entry for this variant (Variation ID: 162797). Experimental studies have shown that this missense change impairs kinase activity of the BRAF protein (PMID: 18413255). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco RCV000767527 SCV001167600 pathogenic Cardiofaciocutaneous syndrome 1 2018-08-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000157831 SCV001247573 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000767527 SCV000898145 pathogenic Cardiofaciocutaneous syndrome 1 2018-09-21 no assertion criteria provided clinical testing
GenomeConnect - CFC International RCV000999624 SCV001156331 not provided Noonan syndrome 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 10-13-2014 by Lab or GTR ID 26957. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000157831 SCV001809483 pathogenic not provided no assertion criteria provided clinical testing

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