ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1722C>G (p.His574Gln)

dbSNP: rs397507481
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033328 SCV000057233 pathogenic not provided 2023-10-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with increased ERK phosphorylation (PMID: 27478040); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 27505666, 34625582, 27478437, 35353015, Luk2013[CaseReport], 27478040)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000677114 SCV000803185 pathogenic Cardiofaciocutaneous syndrome 1 2018-05-22 criteria provided, single submitter research
Ambry Genetics RCV001265848 SCV001444020 likely pathogenic Inborn genetic diseases 2018-01-29 criteria provided, single submitter clinical testing
3billion RCV000677114 SCV002521799 likely pathogenic Cardiofaciocutaneous syndrome 1 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040384). A different missense change at the same codon (p.His614Tyr) has been reported to be associated with BRAF related disorder (ClinVar ID: VCV000044810). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae RCV003539765 SCV004307135 uncertain significance RASopathy 2023-07-30 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 27478040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40384). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 574 of the BRAF protein (p.His574Gln).
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000824924 SCV000965956 likely pathogenic Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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