ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.992G>A (p.Arg331Gln) (rs59301204)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000593819 SCV000065077 pathogenic Primary dilated cardiomyopathy 2019-02-01 criteria provided, single submitter clinical testing The p.Arg331Gln variant in LMNA has been reported in 2 individuals with muscular dystrophy and over 20 individuals with dilated cardiomyopathy (DCM) and segrega ted with at least 10 relatives from these families (Benedetti 2007, Moller 2009, Hazebroek 2015, Hoorntje 2017, Dalin 2017, Wu 2018). Many of these individuals had an additional variant in other DCM-related genes as well as unaffected carri er relatives, which is consistent with the observation that patients with this v ariant tend to have a milder phenotype compared to those with other variants in LMNA (Hoorntje 2017, Hazebroeck 2015). This variant has been identified in 2/112 956 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has be en reported in ClinVar (Variation ID: 48098). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies support an impact on protein function (Hoorntje 2017). In summary, this variant meets criteria to be classified as pat hogenic for autosomal dominant DCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting.
GeneDx RCV000182367 SCV000234690 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The R331Q pathogenic variant in the LMNA gene has been previously reported numerous times in association with DCM both in the presence and absence of arrhythmia, and it has also been reported in association with partial lipodystrophy (Benedetti et al., 2007; Moller et al., 2009; van Spaendonck-Zwarts et al., 2013; Pugh et al., 2014; Hazebroek et al., 2015; Dalin et al., 2017; Hoorntje et al., 2017; Walsh et al., 2017). In addition, R331Q has been found to segregate with disease in multiple families (Hoorntje et al., 2017); haplotype analysis and review of the clinical phenotypes for these families led the authors to include that R331Q is a founder mutation that results in later-onset disease with a more favorable prognosis. Furthermore, R331Q is not observed at a significant frequency in large population cohorts (Lek et al., 2016).The R331Q variant results in a semi-conservative amino acid substitution within the coil 2B region. The arginine at codon 331 participates in an interchain salt bridge, and structural studies suggest that R331Q has a negative effect on lamin dimer stability (Gangemi et al., 2013). Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Lastly, missense variants in the same (R331P) and nearby residues (S326T, S334N, R335W, R336Q) have been reported in HGMD in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000182367 SCV000706057 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769727 SCV000901148 likely pathogenic Cardiomyopathy 2017-01-23 criteria provided, single submitter clinical testing

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