ClinVar Miner

Submissions for variant NM_014845.6(FIG4):c.1474C>T (p.Arg492Cys)

gnomAD frequency: 0.00002  dbSNP: rs747284213
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001858532 SCV002301520 uncertain significance Charcot-Marie-Tooth disease type 4 2022-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 492 of the FIG4 protein (p.Arg492Cys). This variant is present in population databases (rs747284213, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 694984). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Preventiongenetics, part of Exact Sciences RCV003411830 SCV004107821 uncertain significance FIG4-related condition 2022-12-19 criteria provided, single submitter clinical testing The FIG4 c.1474C>T variant is predicted to result in the amino acid substitution p.Arg492Cys. To our knowledge, this variant has not been reported in the literature. A different variant affecting the same amino acid (p.Arg492Pro) was reported in the compound heterozygous state in a family with cerebral hypomyelination (Lenk et al. 2019. PubMed ID: 30740813). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-110086255-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genesis Genome Database RCV000857166 SCV000999747 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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