ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1390A>G (p.Met464Val) (rs200262654)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772026 SCV000904982 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the lamin tail domain of the LMNA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/276532 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725643 SCV000701060 uncertain significance not provided 2017-05-24 criteria provided, single submitter clinical testing
GeneDx RCV000725643 SCV000590650 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing The M464V variant in the LMNA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M464V variant is observed in 5/9368 (0.05%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The M464V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M464V as a variant of uncertain significance.
Invitae RCV000800973 SCV000940720 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 464 of the LMNA protein (p.Met464Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs200262654, ExAC 0.05%). This variant has not been reported in the literature in individuals with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 432879). 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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