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 2018-11-13 criteria provided, single submitter clinical testing The R166P mutation in the LMNA gene has been reported in association with cardiomyopathy (Parks S et al., 2008; Saga A et al., 2009). Parks et al. identified R166P in two unrelated probands with idiopathic DCM, and Saga et al. identified this mutation in one proband with familial cardiomyopathy with advanced atrioventricular block. R166P results in a non-conservative amino acid substitution of a positively charged Arginine residue with a non-polar Proline residue at a position that is conserved across species (Saga A et al., 2009). Furthermore, the NHLBI Exome Sequencing Project reports R166P was not observed in approximately 6,500 individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, the presence of this mutation indicates an increased risk to develop DCM, however, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic.
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 2019-08-21 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 2017-01-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057411 SCV000088524 not provided not provided no assertion provided not provided

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