ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1004G>A (p.Arg335Gln) (rs138592977)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727308 SCV000293396 uncertain significance not provided 2015-12-17 criteria provided, single submitter clinical testing The R335Q variant of uncertain significance in the LMNA gene has been reported in association with DCM; however, no additional clinical information or segregation information was provided (Narula et al., 2012). The R335Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. A missense variant in the same residue (R335W) and missense variants in nearby residues (R331Q, R331P, S334N, R336Q) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. The R335Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727308 SCV000707459 uncertain significance not provided 2017-04-05 criteria provided, single submitter clinical testing
Invitae RCV000653901 SCV000775791 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 335 of the LMNA protein (p.Arg335Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138592977, ExAC 0.01%). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 23062543, 28416588, 28790152). ClinVar contains an entry for this variant (Variation ID: 246074). 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. A different missense substitution at this codon (p.Arg335Trp) has been determined to be pathogenic (PMID: 24503780, 22224630, 27532257, 27723096). This suggests that the arginine residue is critical for LMNA protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000771975 SCV000904929 uncertain significance Cardiomyopathy 2019-12-19 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001174248 SCV001337378 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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