Submissions for variant NM_170707.4(LMNA):c.1003C>T (p.Arg335Trp) (rs386134243)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	RCV000030145	SCV000052800	likely pathogenic	Primary dilated cardiomyopathy	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000844672	SCV000064996	pathogenic	Primary dilated cardiomyopathy; Laminopathy	2018-04-06	criteria provided, single submitter	clinical testing	The p.Arg335Trp variant in LMNA (ClinVar ID: 36473) was absent from large popula tion studies and has been reported in 9 individuals with a range of phenotypes, all consistent with a laminopathy (1 individual with Emery-Dreifuss muscular dys trophy (EDMD), 1 individual with acro-osteolysis, atrial fibrillation, hypertrig lyceridemia and autoimmune thyroiditis, 1 individual with hand-heart syndrome IV (HHS-IV), and 5 individuals with DCM with or without arrhythmia) (Drouin 2004, Zafeiriou 2005, Lakdawala 2012, Stallmeyer 2012, Walsh 2016, Nishiuchi 2017, Zar agoza 2017). The variant segregated with disease in 7 individuals (HHS-IV: 3 mem bers of 1 family [Zaragoza 2017], DCM+arrhythmia: 3 members of 3 families [Stall meyer 2012, Nishiuchi 2017, LMM data], EDMD: 1 member of 1 family [Zafeiriou 200 5. In vitro protein modeling provides some evidence that the p.Arg335Trp variant may impact protein function (Bollati 2012). In summary, this variant meets crit eria to be classified as pathogenic for laminopathy in an autosomal dominant man ner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS4_Moderate; PP3; PS3_Supporti ng.
GeneDx	RCV000182368	SCV000234691	pathogenic	not provided	2018-01-18	criteria provided, single submitter	clinical testing	The R335W variant in the LMNA gene has been previously reported in multiple individuals in association with DCM (Makiyama et al., 1998; Lakdawala et al., 2012; Stallmeyer et al., 2012; Pugh et al., 2014; Adler et al., 2016; Walsh et al., 2017). It is reported to segregate with DCM in two relatives from two different families (Stallmeyer et al., 2012; ClinVar SCV000064996.4; Landrum et al, 2016), and was also found to segregate with DCM in one relative from a separate family tested at GeneDx. Most recently, R335W was reported to segregate with disease in several affected members of a family with a history of Heart-Hand syndrome IV: Slovenian type, a condition characterized by DCM, arrhythmia, and brachydactyly (Zaragoza et al., 2017). Furthermore, R335W is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), and is classified as a likely pathogenic variant in ClinVar by two additional clinical laboratories in association with DCM (ClinVar SCV000234691.3, SCV000064996.4; Landrum et al, 2016). This variant is also a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, R335W occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, R335W in the LMNA gene is interpreted as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics	RCV000515373	SCV000611277	pathogenic	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysplasia with type A lipodystrophy; Limb-girdle muscular dystrophy, type 1B; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000546102	SCV000657788	pathogenic	Charcot-Marie-Tooth disease, type 2	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 335 of the LMNA protein (p.Arg335Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs386134243, ExAC no frequency). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 22224630, 27532257). This variant has been reported to segregate with brachydactyly and cardiomyopathy in a single family (PMID: 27723096). ClinVar contains an entry for this variant (Variation ID: 36473). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000620788	SCV000736761	likely pathogenic	Cardiovascular phenotype	2019-03-11	criteria provided, single submitter	clinical testing	Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Blueprint Genetics	RCV000182368	SCV000927154	pathogenic	not provided	2017-02-14	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000845456	SCV000987545	pathogenic	Left ventricular noncompaction		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego	RCV000852407	SCV000995090	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-04-09	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001196390	SCV001366997	pathogenic	Primary dilated cardiomyopathy; Mitral regurgitation; Reduced ejection fraction; Ventricular tachycardia	2019-09-24	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
OMIM	RCV000721960	SCV000853099	pathogenic	Heart-hand syndrome, Slovenian type	2018-11-19	no assertion criteria provided	literature only