ClinVar Miner

Submissions for variant NM_002880.4(RAF1):c.683C>G (p.Ser228Cys)

gnomAD frequency: 0.00001  dbSNP: rs766437069
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000179852 SCV000232169 uncertain significance not provided 2014-06-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001046375 SCV001210274 uncertain significance RASopathy 2024-09-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the RAF1 protein (p.Ser228Cys). This variant is present in population databases (rs766437069, gnomAD 0.003%). This missense change has been observed in individual(s) with neonatal testicular torsion (PMID: 30904638). ClinVar contains an entry for this variant (Variation ID: 198487). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters RAF1 gene expression (PMID: 30904638). 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 RCV002362924 SCV002666651 uncertain significance Cardiovascular phenotype 2020-02-26 criteria provided, single submitter clinical testing The p.S228C variant (also known as c.683C>G), located in coding exon 6 of the RAF1 gene, results from a C to G substitution at nucleotide position 683. The serine at codon 228 is replaced by cysteine, an amino acid with dissimilar properties. This variant was detected in affected individuals in a family with testicular torsion and cryptorchidism, and biopsy of testicular tissue from an affected individual indicated reduced Raf-1 and pERK protein expression (Kohn TP et al. Urology, 2019 07;129:60-67). This amino acid position is well 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.

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