ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.398G>A (p.Arg133Gln) (rs60864230)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182356 SCV000234669 likely pathogenic not provided 2017-07-05 criteria provided, single submitter clinical testing A likely pathogenic variant has been identified in the LMNA gene. The R133Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported in other individuals referred for cardiomyopathy testing at GeneDx. This variant has also been reported in the ClinVar Database by an outside laboratory as likely pathogenic in association with Charcot- Marie-Tooth disease (ClinVar SCV000262236.1; Landrum et al., 2016). The R133Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R133Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, this substitution occurs at a position where only amino acids with similar properties to Glutamine are tolerated across species. Lastly, a likely pathogenic variant at the same residue (R133L) has been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014). However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000204542 SCV000262236 pathogenic Charcot-Marie-Tooth disease, type 2 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 133 of the LMNA protein (p.Arg133Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with cardiomyopathy in a single family (Invitae). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with myopathic gait, elevated CK, and muscle weakness (Invitae). ClinVar contains an entry for this variant (Variation ID: 200934). 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 additional missense substitutions at this codon (p.Arg133Leu and p.Arg133Pro) are reported to be deleterious (PMID: 11503164, 12629077, 12927431, 14615128, 16174718). This suggests that the arginine residue is critical for LMNA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182356 SCV000280182 likely pathogenic not provided 2015-10-19 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg133Gln When we initially reviewed the variant in 2011 it was discussed at a the Stanford Center for Inherited Cardiovascular Disease team meeting and we felt that the absence in controls, supporting segregation data, and other variants at the same codon were all sufficient to consider it likely pathogenic, though we would have preferred even more data supporting pathogenicity. Other variants in this gene have been associated with familial dilated cardiomyopathy, often with a higher incidence of conduction system disease, atrial arrhythmias, ventricular ectopy, and sudden death, all of which may occur prior to apparent LV dilatation or dysfunction. Variants in LMNA have also been associated with a wide range of other conditions, including Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy, both of which often have cardiac involvement. Other conditions associated with this gene include Charcot-Marie-Tooth disease, Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome. These don't classically have cardiac involvement, but in some cases they do. Segregation data from our center includes a family in which the variant segregates with disease in three affected siblings (though two of the three siblings are identical twins) and the affected child of one of those siblings. Other variants at this same codon and the neighboring codon have been reported in association with disease. Brown et al (2001) reported p.Arg133Pro in an individual with limb-girdle muscular dystrophy who was diagnosed at 7 years of age. Her cardiac phenotype was noted to include atrial fibrillation and a pacemaker at 32 years of age. A different variant at this codon, p.Arg133Leu, has been reported in three unrelated cases with a progeroid phenotype (Chen et al 2003, Caux et al 2003). In one of those cases the variant was de novo. One of these individuals had hypertrophic cardiomyopathy and skeletal muscle hypertrophy. Lupsa et al 2010 reported a 9yo boy with lipodystrophy and p.Arg133Leu with dilated cardiomyopathy. Another variant at a neighboring codon (p.Ala132Pro) has been reported in association with dilated cardiomyopathy (Karkkainen et al 2006). p.Arg133Gln is a semi conservative amino acid change with a polar, positive Arginine replaced with a polar, neutral Glutamine. In silico analysis with PolyPhen2 predicts the variant to be possibly damaging. Many other variants in the same domain have been reported in association with dilated cardiomyopathy (Pasotti et al 2008). There is no variation at codon 133 listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 16th, 2015). Mean coverage is >50.

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