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

dbSNP: rs59332535

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000201012	SCV000255788	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2015-05-15	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000057453	SCV000337253	pathogenic	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Institute Of Molecular Biology And Genetics, Federal Almazov National 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	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 249 of the LMNA protein (p.Arg249Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Emery-Dreifuss muscular dystrophy or limb-girdle muscular dystrophy (PMID: 10739764, 20980393, 21632249, 22883396). ClinVar contains an entry for this variant (Variation ID: 66931). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (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 and Genomics, 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 National Medical Research Centre	RCV000201012	SCV001548550	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2021-03-20	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814042	SCV001755604	likely pathogenic	Abnormality of the musculature	2021-07-10	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)
Revvity Omics, Revvity	RCV000057453	SCV002017153	pathogenic	not provided	2019-11-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057453	SCV002496938	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	LMNA: PM1, PM2, PM6, PS4:Moderate, PP4, PS3:Supporting
MGZ Medical Genetics Center	RCV000201012	SCV002580387	likely pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2021-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230389	SCV003928722	pathogenic	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.746G>A (p.Arg249Gln) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes (gnomAD). c.746G>A has been reported in the literature in multiple individuals affected with with autosomal dominant Emery-Dreifuss muscular dystrophy or limb-girdle muscular dystrophy (examples: di Barletta2000, Emerson_2009, Mitsuhashi_2010, Komaki_2011, and Coutance_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and reported this variant alteres the normal protein function (Emerson_2009). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=8)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057453	SCV001952776	likely pathogenic	not provided		no assertion criteria provided	clinical testing