ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.722C>T (p.Thr241Met) (rs387906660)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033281 SCV000057186 pathogenic not provided 2021-07-31 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15488754, 16439621, 17603483, 24957944, 15520807, 29493581, 32369273, 30525188, 30414707, 28991257, 24803665, 19206169)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211753 SCV000061620 pathogenic Noonan syndrome 2017-11-02 criteria provided, single submitter clinical testing The p.Thr241Met variant in BRAF has been previously reported in 3 individuals wi th clinical features of Noonan syndrome, including 2 de novo occurrences (LMM da ta, Sarkozy 2009, ClinVar Variation ID 29805). It has also been identified in 1/ 124756 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs387906660). Furthermore, 3 other missense vari ants at position p.241 (p.Thr241Arg, p.Thr241Pro, p.Thr241Lys) have been identif ied in individuals with clinical features of Noonan syndrome, Cardio-facio-cutan eous syndrome, LEOPARD, or Costello syndrome (Sarkozy 2009, LMM data), suggestin g that changes at this position are not tolerated. In summary, the p.Thr241Met v ariant meets criteria to be classified as pathogenic for Noonan syndrome in an a utosomal dominant manner. ACMG/AMP Criteria applied: PM5_Strong; PM6_Strong; PM2 ; PP2.
Fulgent Genetics,Fulgent Genetics RCV000515432 SCV000611252 pathogenic Cardiofaciocutaneous syndrome 1; Lung carcinoma; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000545320 SCV000659079 pathogenic Rasopathy 2020-02-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 241 of the BRAF protein (p.Thr241Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Noonan Syndrome (PMID: 19206169). ClinVar contains an entry for this variant (Variation ID: 29805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Thr241Pro) has been determined to be pathogenic in individuals affected with Cardio-facio-cutaneous (CFC) syndrome (PMID: 17704260, 18042262, 23950000). This suggests that the threonine residue is critical for BRAF protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000022678 SCV000803610 likely pathogenic Noonan syndrome 7 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Noonan syndrome 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:19206169). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Blueprint Genetics RCV000033281 SCV000927841 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV001329218 SCV001520593 pathogenic Cardiofaciocutaneous syndrome 1 2019-03-22 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in one patient with Noonan syndrome [PMID 19206169] Muscle weakness and peripheral neuropathy have been reported in individuals with CFC1 [PMID 16007634, 17437909, 22907230]
OMIM RCV000022678 SCV000043967 pathogenic Noonan syndrome 7 2009-04-01 no assertion criteria provided literature only
GeneReviews RCV000208540 SCV000264341 pathogenic Noonan syndrome 1 2016-02-25 no assertion criteria provided literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000033281 SCV001808076 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000033281 SCV001952678 pathogenic not provided no assertion criteria provided clinical testing

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