ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1517A>C (p.His506Pro) (rs878855233)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227241 SCV000291550 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 506 of the LMNA protein (p.His506Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with dilated cardiomyopathy (DCM) (PMID: 27813223). ClinVar contains an entry for this variant (Variation ID: 242003). Experimental studies have shown that this variant impacts the interaction between prelamin A and Ankrd2, and leads to altered Ankrd2 cellular localization (PMID: 28531892). 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.
GeneDx RCV000235371 SCV000292723 uncertain significance not provided 2015-06-04 criteria provided, single submitter clinical testing The H506P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H506P variant was not observed in approximately 6500 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 H506P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in most mammals, however Proline is the wild type residue at this position in platypus and Alanine is present at this position in alpaca. Missense mutations in this residue (H506D) and nearby residues (W498R, W498C, L512P) have been reported in the Human Gene Mutation Database in association with metabolic laminopathy, muscular dystrophy and myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Center for Human Genetics,University of Leuven RCV000498163 SCV000579568 uncertain significance Hypertrophic cardiomyopathy 2017-04-30 criteria provided, single submitter clinical testing
Color RCV000777786 SCV000913764 uncertain significance Cardiomyopathy 2018-06-27 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, in a region involved in interaction with multiple proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that this variant impacts the interaction between prelamin A and Ankrd2 and leads altered Ankrd2 cellular localization (PMID: 28531892). However, the clinical significance of these observations is not clear. This variant has been reported in an individual affected with dilated cardiomyopathy (Visser 2016), in an individual affected with hypertrophic cardiomyopathy (PMID: 29255176), and in an individual affected with Emery-Dreifuss Muscular Dystrophy). This variant has also been identified in 9/276856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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