Submissions for variant NM_030962.3(SBF2):c.4522C>T (p.Arg1508Cys) (rs141108330)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000713001	SCV000843564	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000713001	SCV000565518	uncertain significance	not provided	2018-10-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SBF2 gene. The R1508C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1508C variant is observed in 7/6606 (0.1%) alleles from individuals of European Finnish background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)]. The R1508C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina	RCV000528673	SCV000375042	uncertain significance	Charcot-Marie-Tooth disease type 4	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000528673	SCV000657964	uncertain significance	Charcot-Marie-Tooth disease type 4	2018-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 1508 of the SBF2 protein (p.Arg1508Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs141108330, ExAC 0.1%) but has not been reported in the literature in individuals with an SBF2-related disease. ClinVar contains an entry for this variant (Variation ID: 306583). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.