ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.497G>C (p.Arg166Pro) (rs267607570)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057411 SCV000234672 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing Reported in ClinVar as a pathogenic and likely pathogenic variant (ClinVar Variant ID# 66901; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in abnormal nuclear morphology and mislocalization of Lamin A (Cowan et al., 2010); This variant is associated with the following publications: (PMID: 26084686, 31383942, 31514951, 20160190, 24846508, 26199943, 18585512, 19638735, 23582089, 26567375, 22337857, 32719615)
Genetic Services Laboratory, University of Chicago RCV000503619 SCV000595618 likely pathogenic Dilated cardiomyopathy 1A 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000556738 SCV000657815 pathogenic Charcot-Marie-Tooth disease, type 2 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 166 of the LMNA protein (p.Arg166Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (rs267607570, ExAC no frequency). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18585512, 26084686) and an individual affected with familial cardiomyopathy with advanced atrioventricular block (PMID: 19638735). ClinVar contains an entry for this variant (Variation ID: 66901). Experimental studies have shown that this missense change results in abnormally shaped nuclei and nuclear envelope-associated LMNA aggregates (PMID: 20160190). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620401 SCV000736990 likely pathogenic Cardiovascular phenotype 2020-09-18 criteria provided, single submitter clinical testing The p.R166P variant (also known as c.497G>C), located in coding exon 2 of the LMNA gene, results from a G to C substitution at nucleotide position 497. The arginine at codon 166 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in unrelated probands with dilated cardiomyopathy (DCM), and familial cardiomyopathy with advanced atrioventricular block (Parks SB et al. Am Heart J. 2008;156(1):161-9; Saga A et al. Tohoku J Exp Med. 2009;218(4):309-16; Begay RL et al. J Am Heart Assoc. 2015 Nov;4(11)). In addition, one in vitro study using a GFP-Lamin A fusion construct suggests this variant results in altered nuclear morphology and localization (Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14). This amino acid position is highly conserved in mammals, but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057411 SCV000088524 not provided not provided no assertion provided not provided

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