Submissions for variant NM_002880.4(RAF1):c.1871C>G (p.Ser624Cys)

dbSNP: rs1057524239

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000678309	SCV000534967	likely pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing	The S624C variant in the RAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S624C 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 S624C 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S624C as a likely pathogenic variant.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678309	SCV000804368	uncertain significance	not provided	2018-02-26	criteria provided, single submitter	provider interpretation	This variant was identified in a 3 year male with autism spectrum disorder and tall stature. Clinical features were not consistent with a Noonan-spectrum disorder. The variant is inherited from a father with no development delay, psychiatric illness, or other relevant history. Subsequent cardiology evaluation was normal and the father had a normal cardiac stress test with echocardiogram. This variant is absent from the gnomAD database and computational prediction models are inconsistent. It has not been previously reported in the literature, to our knowledge.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051449	SCV001215603	uncertain significance	RASopathy	2022-08-23	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 624 of the RAF1 protein (p.Ser624Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 391813).
Mayo Clinic Laboratories, Mayo Clinic	RCV000678309	SCV001714079	likely pathogenic	not provided	2019-07-08	criteria provided, single submitter	clinical testing	PS4_Supporting PM1, PM2, PP2, PP3
3billion	RCV004725217	SCV005328721	likely benign	LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN	2024-09-20	criteria provided, single submitter	clinical testing	The variant was identified in at least one patient who was diagnosed with a different variant in another gene and showed no symptoms related to the gene containing the variant in question.