ClinVar Miner

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

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Total submissions: 11
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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 The p.R335W variant (also known as c.1003C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 1003. The arginine at codon 335 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the Coil2 domain. This variant has been reported in multiple individuals with dilated cardiomyopathy (DCM) (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Stallmeyer B et al. Genet Test Mol Biomarkers, 2012 Jun;16:543-9; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). In addition, this variant has been reported to segregate with disease in a family with Heart-Hand syndrome type IV, whose symptoms included DCM and brachydactyly (Zaragoza MV et al. Clin. Genet., 2017 Mar;91(3):499-500). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 Dilated cardiomyopathy 1A 2019-09-24 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3,PP4.
OMIM RCV000721960 SCV000853099 pathogenic Heart-hand syndrome, Slovenian type 2018-11-19 no assertion criteria provided literature only

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