Submissions for variant NM_002880.4(RAF1):c.1913C>T (p.Thr638Met)

gnomAD frequency: 0.00004  dbSNP: rs730881007

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159092	SCV000209035	uncertain significance	not provided	2014-07-16	criteria provided, single submitter	clinical testing	p.Thr638Met (ACG>ATG): c.1913 C>T in exon 17 of the RAF1 gene (NM_002880.3). A variant of unknown significance has been identified in the RAF1 gene. The T638M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T638M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T638M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, missense mutations in nearby residues have not been reported indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in CARDIOMYOPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226660	SCV000287740	uncertain significance	RASopathy	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 638 of the RAF1 protein (p.Thr638Met). This variant is present in population databases (rs730881007, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181515). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt RAF1 function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000618752	SCV000736737	uncertain significance	Cardiovascular phenotype	2024-09-20	criteria provided, single submitter	clinical testing	The p.T638M variant (also known as c.1913C>T), located in coding exon 16 of the RAF1 gene, results from a C to T substitution at nucleotide position 1913. The threonine at codon 638 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328340	SCV001519419	likely benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.1913C>T (p.Thr638Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251270 control chromosomes. The observed variant frequency is approximately 1.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1913C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000159092	SCV005890298	uncertain significance	not provided	2024-12-01	criteria provided, single submitter	clinical testing