ClinVar Miner

Submissions for variant NM_000117.2(EMD):c.671C>T (p.Pro224Leu) (rs782559230)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183446 SCV000235906 uncertain significance not provided 2013-10-23 criteria provided, single submitter clinical testing p.Pro224Leu c.671 CCG>CTG in exon 6 of the EMD gene (NM_000117.2): The Pro224Leu variant in the EMD gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro224Leu was not observed in approximately 5000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Pro224Leu variant results in a semi-conservative amino acid substitution resulting in the removal of a sterically-hindered Proline at a position that is conserved across species. In silico analysis predicts Pro224Leu is damaging to the protein structure/function. However, the majority of mutations reported in the EMD gene are truncating changes (nonsense, framshift, splice-site), and Pro224Leu occurs in a region of the gene where no missense mutations in nearby residues have been reported. With the clinical and molecular information available at this time, we cannot definitively determine if Pro224Leu is a disease-causing mutation or a rare benign variant. This result cannot be interpreted for diagnosis or used for family member screening at this time. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000638226 SCV000759712 uncertain significance Emery-Dreifuss muscular dystrophy 1, X-linked 2017-08-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 224 of the EMD protein (p.Pro224Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs794729015, ExAC 0.03%). This variant has not been reported in the literature in individuals with EMD-related disease. ClinVar contains an entry for this variant (Variation ID: 201777). 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: "Probably 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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