ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp) (rs267607555)

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Total submissions: 6
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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 2 2015-08-17 criteria provided, single submitter clinical testing
Invitae RCV000653911 SCV000775801 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 349 of the LMNA protein (p.Arg349Trp). 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 (ExAC no frequency). This variant has been reported to segregate in a family affected with partial lipodystrophy and renal disease (PMID: 24080738) 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 (PMID:18035086, 28620495, 23349452, 28641778, 22700598). ClinVar contains an entry for this variant (Variation ID: 66762). 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 and their clinical significance is uncertain. Two different missense substitutions at this codon (p.Arg349Gln and p.Arg349Leu) have been reported in individuals affected with dilated cardiomyopathy (PMID: 27532257, 25163546, 15219508). This suggests that the arginine residue is critical for LMNA protein function. 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
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; Limb-girdle muscular dystrophy, type 1B; Congenital muscular dystrophy, LMNA-related; 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.

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