ClinVar Miner

Submissions for variant NM_030962.3(SBF2):c.3831C>G (p.Ile1277Met) (rs139522696)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000713000 SCV000843563 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000713000 SCV000293902 uncertain significance not provided 2018-01-31 criteria provided, single submitter clinical testing TThe I1277M variant has been previously reported in an adult female with sporadic CMT1; however, a second SBF2 variant was not identified in the reported individual, and the I1277M variant was classified as unlikely pathogenic by the authors (Hoyer et al., 2014). The I1277M variant is observed in 58/126556 (0.05%) alleles from individuals of Eurpoean background in large population cohorts (Lek et al., 2016). The I1277M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000237027 SCV000596932 uncertain significance not specified 2016-05-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000467056 SCV000375044 uncertain significance Charcot-Marie-Tooth disease type 4 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000467056 SCV000541253 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1277 of the SBF2 protein (p.Ile1277Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs139522696, ExAC 0.03%). This variant has been reported in an individual affected with CMT type 1, but was also reported in an unaffected control individual (PMID: 25025039). ClinVar contains an entry for this variant (Variation ID: 246374). 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: "Benign"; Align-GVGD: "Class C0"). 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.

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