Submissions for variant NM_002880.4(RAF1):c.524A>G (p.His175Arg)

dbSNP: rs397516822

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037693	SCV000061355	pathogenic	Noonan syndrome	2013-05-23	criteria provided, single submitter	clinical testing	The His175Arg variant in the RAF1 gene has not been previously reported in the l iterature. This variant was not identified in either parent of this individual a nd therefore likely occurred de novo, assuming that non-medical explanations inc luding alternate paternity or undisclosed adoption have been ruled out. In addit ion, this variant has been found to segregate with clinical features consistent with Noonan syndrome in four individuals in one family tested by our laboratory. The His175Arg variant has not been identified in large, ethnically-distinct pop ulations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest this variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic based on it s de novo occurrence (http://pcpgm.partners.org/LMM).
Blueprint Genetics	RCV000788414	SCV000927514	pathogenic	not provided	2018-01-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213204	SCV001384825	uncertain significance	RASopathy	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 175 of the RAF1 protein (p.His175Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33673806). ClinVar contains an entry for this variant (Variation ID: 40594). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt RAF1 function with a positive predictive value of 95%. 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001254110	SCV001430040	pathogenic	Noonan syndrome 5	2020-05-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362668	SCV004054141	likely pathogenic	Cardiovascular phenotype	2023-09-14	criteria provided, single submitter	clinical testing	The p.H175R variant (also known as c.524A>G), located in coding exon 4 of the RAF1 gene, results from an A to G substitution at nucleotide position 524. The histidine at codon 175 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported to occur de novo in a case with features consistent with Noonan syndrome (NS), and has been reported to segregate with features consistent with NS in a family (external communication). This variant has also been detected in a cohort referred for hypertrophic cardiomyopathy genetic testing; however, details were limited (Hathaway J et al. BMC Cardiovasc Disord. 2021 Mar;21(1):126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000788414	SCV004167640	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 33673806)
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000037693	SCV001438428	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing