ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.673C>T (p.Arg225Ter) (rs60682848)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211792 SCV000065052 pathogenic Primary dilated cardiomyopathy 2011-12-16 criteria provided, single submitter clinical testing The Arg225X variant in LMNA leads to a premature stop at codon 225, which is pre dicted to lead to a truncated or absent protein. This variant has been reported in 4 individuals with variable clinical features that included DCM, conduction s ystem disease, and musculoskeletal abnormalities (Jakobs 2001, Van Tintelen 2007 , Saga 2009, Carboni 2010). These presentations are typical manifestations of pa thogenic LMNA variants. In addition, this variant segregated with disease in at least 7 affected family members and was absent from at least 600 control chromo somes (Jakobs 2001, Van Tintelen 2007, Saga 2009, Carboni 2010). In summary, the Arg225X variant meets our criteria for pathogenicity based on the severity of t he change, segregation in affected individuals, and absence from controls.
GeneDx RCV000057442 SCV000234678 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing The R225X pathogenic variant in the LMNA gene has been previously reported in multiple individuals from various ethnic backgrounds in association with laminopathy (Jakobs et al., 2001; van Tintelen et al., 2007; Saga et al., 2009; Carboni et al., 2010; Siu et al., 2012; Arimura et al., 2013; Pugh et al., 2014; Sato et al., 2016). Additionally, R225X was found to co-segregate with laminopathy phenotypes, including DCM, cardiac conduction disease, and/or limb girdle muscular dystrophy, in several affected relatives from multiple families (Jakobs et al., 2001; van Tintelen et al., 2007; Carboni et al., 2010; Siu et al., 2012; Arimura et al., 2013; Sato et al., 2016). It is also classified as a pathogenic variant in ClinVar by two other clinical laboratories (SCV000065052.4, SCV000247854.1; Landrum et al., 2016), and has been observed in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The R225X variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense mediated mRNA decay. Multiple other nonsense variants in the LMNA gene have been reported in HGMD in association with laminopathy (Stenson et al., 2014). Moreover, functional studies showed that haploinsufficiency of the LMNA protein due to R225X results in accelerated nuclear senescence and apoptosis of cardiomyocytes (Siu et al., 2012). Furthermore, R225X was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R225X in the LMNA gene is interpreted as a pathogenic variant.
Genetic Services Laboratory,University of Chicago RCV000194831 SCV000247854 pathogenic Limb-girdle muscular dystrophy, type 1B 2015-01-09 criteria provided, single submitter clinical testing
Invitae RCV000464494 SCV000548864 pathogenic Charcot-Marie-Tooth disease, type 2 2019-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg225*) in the LMNA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature segregating with disease in several families affected with dilated cardiomyopathy (DCM) with conduction disease and/or limb-girdle muscular dystrophy 1B (LGMD1B) (PMID: 11561226, 23362510, 2280636). This variant has also been reported in other unrelated individuals affected with DCM and/or conduction disease (PMID: 24237251, 18035086). ClinVar contains an entry for this variant (Variation ID: 48074). Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory,University of Chicago RCV000057442 SCV000595598 pathogenic not provided 2013-02-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170453 SCV001333033 pathogenic Cardiomyopathy 2017-11-29 criteria provided, single submitter clinical testing
GeneReviews RCV000056001 SCV000087057 pathologic Dilated cardiomyopathy 1A 2013-09-19 no assertion criteria provided curation Converted during submission to Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057442 SCV000088556 not provided not provided no assertion provided not provided

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