ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.749C>T (p.Ala250Val) (rs397517907)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237089 SCV000293879 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing While the A250V variant has not been published as a pathogenic variant or a benign variant, it has been classified as a likely pathogenic variant by another clinical laboratory in ClinVar (Landrum et al., 2014). The A250V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the A250V 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 that is conserved only in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000707020 SCV000836098 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 250 of the LMNA protein (p.Ala250Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 48078). 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 C55"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041363 SCV000065056 uncertain significance not specified 2018-10-31 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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