ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.566G>A (p.Arg189Gln)

gnomAD frequency: 0.00002  dbSNP: rs766856162
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426904 SCV000535754 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing The R189Q variant in the LMNA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a different missense variant involving the same codon (R189W) was reported in a 55 year old female with dilated cardiomyopathy (DCM) and cardiac conduction abnormalities who had 3 brothers with sudden cardiac death (Botto et al., 2010). The R189W variant was also identified in another proband with DCM and interstitial myocardial fibrosis (Fontana et al., 2013). Additionally, missense variants in nearby residues (E186K, L188R, R190W, R190P, R190Q, D192V, D192G) have been reported in the Human Gene Mutation Database in association with laminopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R189Q variant 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. The R189Q 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 where amino acids with similar properties to Arginine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R189Q as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001184318 SCV001350269 uncertain significance Cardiomyopathy 2023-11-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 189 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 34011823, 34768595). This variant has been identified in 1/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001865396 SCV002217358 uncertain significance Charcot-Marie-Tooth disease type 2 2023-09-10 criteria provided, single submitter clinical testing 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. 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. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). ClinVar contains an entry for this variant (Variation ID: 392479). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 34011823, 34768595). This variant is present in population databases (rs766856162, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 189 of the LMNA protein (p.Arg189Gln).
Fulgent Genetics, Fulgent Genetics RCV002480327 SCV002790457 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; 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 2021-10-09 criteria provided, single submitter clinical testing
KTest Genetics, KTest RCV001594396 SCV001499963 likely pathogenic Dilated cardiomyopathy 1A no assertion criteria provided clinical testing
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University RCV001594396 SCV001593105 likely pathogenic Dilated cardiomyopathy 1A 2021-04-27 no assertion criteria provided clinical testing

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