ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1880G>A (p.Arg627His) (rs745997478)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182375 SCV000234711 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing p.Arg627His (CGC>CAC): c.1880 G>A in exon 11 of the LMNA gene (NM_170707.2). The Arg627His variant in the LMNA gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg627His results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg627His is damaging to the protein structure/function. The Arg627His 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. Nevertheless, no mutations in nearby residues have been reported in association with cardiomyopathy. With the information available at this time, we cannot definitively determine if Arg627His is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769734 SCV000901156 uncertain significance Cardiomyopathy 2016-05-19 criteria provided, single submitter clinical testing
Invitae RCV000801285 SCV000941056 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 627 of the LMNA protein (p.Arg627His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs745997478, ExAC 0.002%). This variant has not been reported in the literature in individuals with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 200948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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.

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