ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.2080A>G (p.Met694Val) (rs143531641)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236139 SCV000294018 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing The M694V variant has been previously reported in two individuals with unspecified CMT who were heterozygous for the variant and did not have a second pathogenic variant on the opposite allele (Nicholson et al., 2011). M694V was subsequently reported as a variant of uncertain significance in a patient with sporadic amyotrophic lateral sclerosis (ALS) who had variants in other genes possibly associated with the phenotype (Cady et al., 2015). It was not observed with any significant frequency in the 1000 Genomes Project or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. The M694V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the 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.
Invitae RCV000796868 SCV000936400 uncertain significance Charcot-Marie-Tooth disease type 4 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 694 of the FIG4 protein (p.Met694Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs143531641, ExAC 0.01%). This variant has been observed in an individual affected with amyotropic lateral sclerosis (ALS), however, that individual also carried variants in other ALS-related genes, so the impact of this variant is uncertain (PMID: 25382069). ClinVar contains an entry for this variant (Variation ID: 246456). 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 and their clinical significance is uncertain. 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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