ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Illumina Clinical Services Laboratory,Illumina RCV001094183 SCV000375044 uncertain significance Charcot-Marie-Tooth disease, type 4B2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000467056 SCV000541253 uncertain significance Charcot-Marie-Tooth disease type 4 2019-10-23 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.
Genetic Services Laboratory,University of Chicago RCV000237027 SCV000596932 uncertain significance not specified 2016-05-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000713000 SCV000843563 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001094183 SCV001473175 uncertain significance Charcot-Marie-Tooth disease, type 4B2 2019-07-25 criteria provided, single submitter clinical testing The SBF2 c.3831C>G; p.Ile1277Met variant (rs139522696), has been reported in the heterozygous state in individuals affected with CMT and in a control individual (Hoyer 2014). However, the p.Ile1277Met variant was not predicted to be associated with CMT. This variant is found in the general population with an overall allele frequency of 0.02 % (60/ 282,692 alleles) in the Genome Aggregation Database. The isoleucine at codon 1277 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ile1277Met variant is uncertain at this time.

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