Submissions for variant NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)

gnomAD frequency: 0.00001  dbSNP: rs267607555

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057218	SCV000234693	pathogenic	not provided	2013-04-11	criteria provided, single submitter	clinical testing	p.Arg349Trp (CGG>TGG): c.1045 C>T in exon 6 of the LMNA gene (NM_170707.2). The Arg349Trp mutation in the LMNA gene has been reported in one individual with atypical partial lipodystrophy (Mory P et al., 2012). In addition, a mutation affecting this same residue, (Arg349Leu), has been reported in three individuals from one family, all of whom required cardiac transplantation at ages 18, 20, and 36 years (Hermida-Prieto M et al., 2004). Mutations in nearby residues (Glu347Lys, Ala350Pro, Gln353Lys) have been reported in association with DCM and conduction defects, further supporting the functional importance of this residue and this region of the protein. Arg349Trp was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Arg349Trp in the LMNA gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Genetic Services Laboratory, University of Chicago	RCV000500548	SCV000595602	pathogenic	Familial partial lipodystrophy, Dunnigan type	2015-08-17	criteria provided, single submitter	clinical testing
Invitae	RCV000653911	SCV000775801	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the LMNA protein (p.Arg349Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lipodystrophy and/or renal disease or dilated cardiomyopathy (PMID: 18035086, 22700598, 23349452, 24080738, 28620495, 28641778). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66762). 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%. This variant disrupts the p.Arg349 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15219508, 25163546, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000754811	SCV000882461	likely pathogenic	Monogenic diabetes	2017-10-27	criteria provided, single submitter	clinical testing	The c.1045C>T variant in codon 349 (exon 6) of the Lamin A/C gene, LMNA, results in the substitution of Arginine to Tryptophan. Mutations in the LMNA gene have been found to cause multiple disorders, collectively known as A-type laminopathies, that have overlapping signs and symptoms (23853504; 20074070; OMIM 150330). A-type laminopathies include familial partial lipodystrophy type 2 (also called familial partial lipodystrophy, Dunnigan type), Limb-Girdle muscular dystrophy type 1B, Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth type 2B1 disease, Hutchinson-Gilford progeria, Heart-hand syndrome, Slovenian type, mandibuloacral dysplasia, Malouf syndrome, and familial dilated cardiomyopathy.1-3 To date, no clear genotype-phenotype correlations have been identified (23853504; 20074070). The c.1045C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the p.Arg349Trp substitution has been identified in patients with skeletal, cardiac and metabolic phenotypes (23853504; 24080738; 2270059). The c.1045C>T variant has been identified in multiple affected individuals in four generations of a family with familial partial lipodystrophy4, as well as in an 18-year old boy with atypical partial lipodystrophy as a de novo change (2270059). A different amino acid change at this same residue, p.Arg349Leu, was identified in a mother and two daughters with dilated cardiomyopathy (15219508). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PM2, PM6, PP1, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000057218	SCV001715570	pathogenic	not provided	2020-07-24	criteria provided, single submitter	clinical testing	PS4, PP1_strong, PM2, PM5, PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000500548	SCV002072991	likely pathogenic	Familial partial lipodystrophy, Dunnigan type		criteria provided, single submitter	clinical testing	The missense variant p.R349W in LMNA (NM_170707.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported to segregate in a family affected with partial lipodystrophy and renal disease (Thong et al., 2013) and has been reported in individuals with lipodystrophy with and without renal disease or dilated cardiomyopathy including one individual in whom the variant was de novo (Tintelen et al., 2007; Fountas et al., 2017; van SpaendonckZwarts et al., 2013; Akinci et al., 2017; Mory et al., 2012). The p.R349W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene LMNA contains 112 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504959	SCV002815071	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, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-10-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996495	SCV004827207	uncertain significance	Primary dilated cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 349 in the intermediate filament rod domain of the lamin A/C protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18035086, 23183350, 23349452, 27813223, 28790152, 31521807) and in individuals affected with unspecified cardiomyopathy (PMID: 28679633, 31383942). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to the insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. However, this variant has also been reported in individuals affected with familial partial lipodystrophy, both with and without cardiac involvement (PMID: 22700598, 24080738, 28620495, 28641778, 31794942, 32413188, 32517491, 32939435, 36397776). This variant segregated with disease in multiple individuals affected with familial partial lipodystrophy, both with and without cardiac involvement, in one extended family (PMID: 24080738). It has also been reported in individuals affected with atypical progeroid syndrome with partial lipodystrophy and cardiac abnormalities (PMID: 35384599). Familial partial lipodystrophy is a rare autosomal dominant condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis, as well as various cardiovascular complications. We recommend you discuss this finding with your healthcare provider. Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause familial partial lipodystrophy (ClinVar variation ID: 66762).
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057218	SCV000088331	not provided	not provided		no assertion provided	not provided
GenomeConnect, ClinGen	RCV000845011	SCV000986842	not provided	Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Hutchinson-Gilford syndrome; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 09/04/2018 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.