Submissions for variant NM_002880.4(RAF1):c.1150C>G (p.Pro384Ala)

gnomAD frequency: 0.00001  dbSNP: rs140788943

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680666	SCV000808110	uncertain significance	not provided	2018-08-21	criteria provided, single submitter	clinical testing	The P384A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 1/8726 (0.01%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The P384A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nonetheless, additional evidence is needed to clarify pathogenicity, including observation in a significant number of affected individuals, segregation data, and functional evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821912	SCV000962686	uncertain significance	RASopathy	2022-06-15	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. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 561376). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. This variant is present in population databases (rs140788943, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 384 of the RAF1 protein (p.Pro384Ala).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813542	SCV002060844	uncertain significance	Noonan syndrome and Noonan-related syndrome	2018-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004026164	SCV005019637	uncertain significance	Cardiovascular phenotype	2023-11-01	criteria provided, single submitter	clinical testing	The p.P384A variant (also known as c.1150C>G), located in coding exon 10 of the RAF1 gene, results from a C to G substitution at nucleotide position 1150. The proline at codon 384 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594093	SCV005087119	likely benign	Noonan syndrome 5	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Gain of function is associated with Noonan (MIM#611553) and LEOPARD syndromes (MIM#2611554), while loss of function is associated with non-HCM-associated variants (PMIDs: 17603483, 17603482). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Pro384Ser) and p.(Pro384Arg) have been classified as variants of uncertain significance by clinical laboratories in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical laboratories in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I)