Submissions for variant NM_170707.4(LMNA):c.497G>C (p.Arg166Pro)

dbSNP: rs267607570

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057411	SCV000234672	pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in abnormal nuclear morphology and mislocalization of Lamin A (Cowan et al., 2010); This variant is associated with the following publications: (PMID: 26084686, 31383942, 31514951, 24846508, 26199943, 18585512, 19638735, 23582089, 26567375, 22337857, 32719615, 20160190, 33242466, 34045587, 34862408, 10939567)
Genetic Services Laboratory, University of Chicago	RCV000503619	SCV000595618	likely pathogenic	Dilated cardiomyopathy 1A	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000556738	SCV000657815	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 166 of the LMNA protein (p.Arg166Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial cardiomyopathy with advanced atrioventricular block and dilated cardiomyopathy (PMID: 18585512, 19638735, 26084686). ClinVar contains an entry for this variant (Variation ID: 66901). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000620401	SCV000736990	likely pathogenic	Cardiovascular phenotype	2023-11-01	criteria provided, single submitter	clinical testing	The p.R166P variant (also known as c.497G>C), located in coding exon 2 of the LMNA gene, results from a G to C substitution at nucleotide position 497. The arginine at codon 166 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in unrelated probands with dilated cardiomyopathy (DCM), and familial cardiomyopathy with advanced atrioventricular block (Parks SB et al. Am Heart J. 2008;156(1):161-9; Saga A et al. Tohoku J Exp Med. 2009;218(4):309-16; Begay RL et al. J Am Heart Assoc. 2015 Nov;4(11)). In addition, one in vitro study using a GFP-Lamin A fusion construct suggests this variant results in altered nuclear morphology and localization (Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV003993783	SCV004812377	likely pathogenic	Primary dilated cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in LMNA is predicted to replace arginine with proline at codon 166, p.(Arg166Pro). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the coil 1B domain. There is a large physicochemical difference between arginine and proline. This variant is present in a single Europrean (non-Finnish) individual from the population database gnomAD v3.1. This variant has been reported in at least four probands with a phenotype suggestive of LMNA-related cardiomyopathy which includes dilated cardiomyopathy and arrhythmia and/or conduction system disease (PMID: 18585512, 19638735, 30739589). The variant has been reported to segregate with cardiomyopathy in affected family members from one family (PMID: 33029862). Nuclear aggregation assays in cell lines showed increased aggregation indicating that this variant impacts protein function (PMID: 20160190, 34862408). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PS3_Moderate, PM2_Supporting, PP1, PP3.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057411	SCV000088524	not provided	not provided		no assertion provided	not provided