ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.746G>A (p.Arg249Gln) (rs59332535)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201012 SCV000255788 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2015-05-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000057453 SCV000337253 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing
Institute of Molecular Biology and Genetics, Federal Almazov North-West Medical Research Centre RCV000496185 SCV000586698 pathogenic Dilated cardiomyopathy 1A criteria provided, single submitter research The patient 17 years old was diagnosed with paroxysmal atrial fibrillation, nonsustained atrial tachycardia and AV conduction abnormalities in combination with frequent ventricular extrasystole. Neurological examination revealed features concomitant with Emery-Dreifuss muscular dystrophy. Genetic investigation revealed R249Q substitution (NP_733821.1) in LMNA gene (rs59332535).
Genetic Services Laboratory, University of Chicago RCV000501991 SCV000595620 pathogenic Muscular dystrophy 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000548477 SCV000657820 pathogenic Charcot-Marie-Tooth disease, type 2 2020-03-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 249 of the LMNA protein (p.Arg249Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs59332535, ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with Emery-Dreifuss muscular dystrophy and a single individual affected with limb-girdle muscular dystrophy (PMID: 10739764, 20980393, 21632249, 22883396). Experimental studies have shown that this missense change leads to changes in emerin–lamin A/C interactions, cell proliferation, and collagen-dependent cell-adhesion (PMID: 19524666). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000662104 SCV000784444 pathogenic Charcot-Marie-Tooth disease type 2B1 2018-03-05 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000057453 SCV001450126 likely pathogenic not provided 2015-05-26 criteria provided, single submitter clinical testing
Institute of Molecular Biology and Genetics, Federal Almazov North-West Medical Research Centre RCV000201012 SCV001548550 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2021-03-20 criteria provided, single submitter clinical testing
GeneDx RCV000057453 SCV001774155 pathogenic not provided 2021-06-24 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 66931; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies indicate R249Q impairs lamin A/C-emerin protein interaction, as well as increases cell proliferation and adhesion to collagen (Emerson et al., 2009); This variant is associated with the following publications: (PMID: 26582918, 19524666, 27708273, 10939567, 12649505, 32793522, 27535533, 32659731, 32571898, 31862442, 31498906, 27363342, 29893365, 29057633, 28398466, 29693488, 28877744, 10739764, 12032588, 21632249, 20980393, 22883396)
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057453 SCV000088567 not provided not provided no assertion provided not provided
Clinical Genetics,Academic Medical Center RCV000057453 SCV001923751 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000057453 SCV001952776 likely pathogenic not provided no assertion criteria provided clinical testing

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