ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.569G>A (p.Arg190Gln) (rs267607571)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619042 SCV000736056 uncertain significance Cardiovascular phenotype 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768712 SCV000900082 pathogenic Cardiomyopathy 2017-10-05 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057421 SCV000088535 not provided not provided no assertion provided not provided
GeneDx RCV000057421 SCV000234675 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing The R190Q pathogenic variant in the LMNA gene has been reported in several individuals with DCM, most of whom also had a history of arrhythmia (Parks et al., 2008; Perrot et al., 2009; Garcia-Pavia et al., 2013). R190Q was initially reported in association with DCM when Parks et al. (2008) described a 53 year-old male with an ejection fraction of 29%, 1st-degree atrioventricular block, bigeminy, and bradycardia. Although neither of his children were symptomatic, they both harbored the R190Q variant and had signs of arrhythmia or cardiomyopathy upon clinical evaluation (Parks et al., 2008). Of note, R190Q has also been identified in an individual with Emery-Dreifuss muscular dystrophy type 2 (EDMD2); however, this individual was found to harbor a second variant in the same LMNA allele that has been previously published in association with EDMD2 (Cenni et al., 2005). While functional studies on this individual's tissue demonstrated a reduction in phosphorylation in their myoblasts and a slightly reduced level of lamin A/C expression in their mature muscle fibers, it is not possible to discern which LMNA variant is responsible for these results (Cenni et al., 2005). Nevertheless, the pathogenicity of R190Q was independently supported when Cowen et al. (2010) demonstrated that COS7 cells expressing GFP-prelamin A fusion constructs including the R190Q variant showed mild-moderate levels of abnormal nuclear shapes in addition to a significantly greater proportion of nuclei with nuclear envelope-associated aggregates compared to control COS7 cells. The R190Q variant results in a semi-conservative amino acid substitution of Arginine to Glutamine at a position that is conserved across species. Variants in the same residue (R190Q, R190P) have been reported in HGMD in association with DCM (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Moreover, the R190Q pathogenic variant was not observed in either the Exome Aggregation Consortium or 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. In summary, R190Q in the LMNA gene is interpreted as a pathogenic variant.
Invitae RCV000653887 SCV000775777 pathogenic Charcot-Marie-Tooth disease, type 2 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 190 of the LMNA protein (p.Arg190Gln). 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 reported in several individuals with dilated cardiomyopathy (DCM) and segregated with DCM and/or conduction disease in one family (PMID: 20160190, 26899768, 18795223). ClinVar contains an entry for this variant (Variation ID: 66910). Experimental studies have shown that this missense change is associated with abnormal localization of lamin A in the nuclear envelope (PMID: 20160190). A different missense substitution at this codon (p.Arg190Trp) has been determined to be pathogenic (PMID: 11897440, 28416588, 23701190, 24386194). 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.

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