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

gnomAD frequency: 0.00002  dbSNP: rs766856162

Total submissions: 8

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.
Labcorp Genetics (formerly Invitae), Labcorp	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; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; 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
All of Us Research Program, National Institutes of Health	RCV004000578	SCV004834755	uncertain significance	Primary dilated cardiomyopathy	2024-07-20	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the intermediate filament rod domain of the LMNA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/30974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Ambry Genetics	RCV004022516	SCV005030838	uncertain significance	Cardiovascular phenotype	2023-10-20	criteria provided, single submitter	clinical testing	The p.R189Q variant (also known as c.566G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 566. The arginine at codon 189 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with dilated cardiomyopathy (DCM) (Ferradini V et al. J Clin Med, 2021 Oct;10; Nguyen TV et al. Circ J, 2021 Aug;85:1469-1478). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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