Submissions for variant NM_030962.3(SBF2):c.3163A>G (p.Ile1055Val) (rs142891020)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757736	SCV000886074	uncertain significance	not provided	2017-11-09	criteria provided, single submitter	clinical testing	The p.Ile1055Val variant (rs142891020) has not been reported in the medical literature, and it is not listed in gene-specific variant databases. The p.Ile1055Val variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.002% (identified in 5 out of 246,176 chromosomes). The isoleucine at codon 1055 is moderately conserved considering 11 species (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Ile1055Val variant cannot be determined with certainty.
Invitae	RCV000544537	SCV000657951	uncertain significance	Charcot-Marie-Tooth disease type 4	2017-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 1055 of the SBF2 protein (p.Ile1055Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs142891020, ExAC 0.004%) but has not been reported in the literature in individuals with an SBF2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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