ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.497G>A (p.Arg166Gln) (rs267607570)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771896 SCV000904660 uncertain significance Cardiomyopathy 2018-08-13 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the intermediate filament rod domain of the LMNA protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the 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 7/203092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position p.Arg166Pro is considered to be disease-causing (Clinvar). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732765 SCV000860751 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing
GeneDx RCV000732765 SCV000293894 uncertain significance not provided 2016-03-03 criteria provided, single submitter clinical testing The R166Q variant in the LMNA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R166Q 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. However the 1000 Genomes Project reports R166Q was observed in 4/186 alleles (2%) from a Chinese subpopulation indicating it may be a rare variant in this population. The R166Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine 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 R166Q as a variant of uncertain significance.
Invitae RCV000653861 SCV000775751 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 166 of the LMNA protein (p.Arg166Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs267607570, ExAC 0.03%). This variant has been observed in an individual affected with congenital muscular dystrophy (PMID: 28688748). ClinVar contains an entry for this variant (Variation ID: 163866). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg166 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 18585512, 26084686, 19638735), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 RCV000150939 SCV000198595 uncertain significance not specified 2014-02-27 criteria provided, single submitter clinical testing The Arg166Gln variant in LMNA has not been previously reported in individuals wi th cardiomyopathy. Data from large European and African American cohorts is insu fficient to assess whether this variant is present in the general population. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. Additional information is needed t o fully assess the clinical significance of the Arg166Gln variant.

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