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

dbSNP: rs267607571

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057421	SCV000234675	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Identified in at least one individual with Emery-Dreifuss muscular dystrophy type 2 (EDMD2); this individual also harbored a second variant in the same LMNA allele, previously published in association with EDMD2 (Cenni et al., 2005; Ditaranto et al., 2019); Published functional studies demonstrated 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 (Cowan et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24846508, Garcia-Pavia2013[Abstract], 34862408, 18795223, 28069705, 26899768, 11897440, 28416588, 23701190, 24386194, 29693488, 29764566, 31447099, 31983221, 31383942, 15744034, 18585512, 30453078, 31744510, 35288587, 20160190, 10939567, 36264615)
Ambry Genetics	RCV000619042	SCV000736056	pathogenic	Cardiovascular phenotype	2021-12-10	criteria provided, single submitter	clinical testing	The p.R190Q pathogenic mutation (also known as c.569G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with dilated cardiomyopathy (DCM) (Parks SB et al. Am. Heart J., 2008 Jul;156:161-9; Perrot A et al. Basic Res. Cardiol., 2009 Jan;104:90-9; Park J et al. Genet Med, 2020 01;22:102-111; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000653887	SCV000775777	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the LMNA protein (p.Arg190Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 18795223, 20160190, 26899768). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66910). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 20160190). This variant disrupts the p.Arg190 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11897440, 23701190, 24386194, 28416588). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768712	SCV000900082	pathogenic	Cardiomyopathy	2020-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768712	SCV001348061	likely pathogenic	Cardiomyopathy	2019-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 190 of the intermediate filament rod domain of the lamin A/C protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes abnormal localization of lamin A in the nuclear envelope (PMID: 20160190). This variant has been reported in two unrelated individuals (PMID: 18795223, 26899768) and three related individuals affected with dilated cardiomyopathy (PMID: 20160190). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position (p.Arg190Trp) is thought to be disease-causing (Clinvar variation ID 66908). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449792	SCV001653073	likely pathogenic	Primary dilated cardiomyopathy	2020-02-13	criteria provided, single submitter	clinical testing	The p.Arg190Gln variant in LMNA has been reported in the heterozygous state in 3 individuals with DCM, and in 2 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC; Cuenta 2016, Parks 2008, Perrot 2009, Poloni 2019, Te Riele 2017). It has also been identified in 1 individual with Emery-Dreifuss muscular dystrophy (EDMD) who harbored a second LMNA variant in cis that has been classified as pathogenic for EDMD (Cenni 2005). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 66910) and was absent from large population studies. In vitro functional studies support an impact on protein function (Cowan 2010) and computational prediction tools and conservation analysis suggest that the p.Arg190Gln variant may impact the protein. Another variant at the same position, p.Arg190Trp has been reported in several individuals with DCM and is classified as pathogenic by several clinical laboratories in ClinVar (Variation ID 66908, Arbustini 2002, Sylvius 2005, Vaikhanskaya 2014). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PM2, PM5, PP3, PS3_Supporting, PS4_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000057421	SCV002103192	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM1, PM2, PM5, PP1, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000768712	SCV002572069	pathogenic	Cardiomyopathy	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.569G>A (p.Arg190Gln) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251370 control chromosomes. c.569G>A has been reported in the literature in multiple individuals affected with familial dilated cardiomyopathy/Lamin A/C cardiomyopathies (example, Parks_2008, Perrot_2009, Cowan_2010, Cuenca_2016, Te Riele_2017, Park_2020, Gerbino_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated membrane bound GFP-lamin A aggregates and nuclear shape abnormalities supporting a pathogenic outcome (Cowan_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000057421	SCV003821006	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447483	SCV004175510	likely pathogenic	Dilated cardiomyopathy 1A	2022-12-13	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057421	SCV000088535	not provided	not provided		no assertion provided	not provided