Submissions for variant NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys)

gnomAD frequency: 0.00001  dbSNP: rs150840924

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000148606	SCV000198614	uncertain significance	Primary dilated cardiomyopathy	2017-05-23	criteria provided, single submitter	clinical testing	The p.Arg435Cys variant in LMNA has been reported in the heterozygous state in 1 adult with DCM and subtle myopic findings (Vytopil 2003) and in the homozygous state in 3 infants with a progeroid syndrome and restrictive dermopathy/skin abn ormalities (Madej-Pilarczyk 2009, Youn 2010, Starke 2013). The 3 infants did not have any cardiovascular features nor did any nor did any of the heterozygous re latives who were tested except one family member had mild signs of hypertensive cardiac disease that was most likely age related. Western blot and tissue immuno -staining analyses revealed the Arg435Cys variant led to progressive loss of LMN A over time associated with increasing DNA double strand breaks and decreased re cruitment of P53 binding protein 1 (53BP1) to DNA-damage sites, suggesting delay ed DNA repair (Madej-Pilarczyk 2009, Starke 2013). This variant has also been id entified in 2/111156 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150840924). Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. In summary, while there is some suspicion for a pathogenic role in progeroid syndrome and/or dermatological abnormalities when p resent in homozygosity, the clinical significance of this variant is uncertain. In addition, there is limited information available to assess if this variant is disease-causing for cardiomyopathy when present in heterozygosity and therefore the clinical significance of this variant for cardiomyopathy is uncertain.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150953	SCV000198615	uncertain significance	Hutchinson-Gilford syndrome	2017-05-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg435Cys variant in LMNA has been reported in the heterozygous state in 1 adult with DCM and subtle myopic findings (Vytopil 2003) and in the homozygous state in 3 infa nts with a progeroid syndrome and restrictive dermopathy/skin abnormalities (Mad ej-Pilarczyk 2009, Youn 2010, Starke 2013). The 3 infants did not have any cardi ovascular features nor did any nor did any of the heterozygous relatives who wer e tested except one family member had mild signs of hypertensive cardiac disease that was most likely age related. Western blot and tissue immuno-staining analy ses revealed the Arg435Cys variant led to progressive loss of LMNA over time ass ociated with increasing DNA double strand breaks and decreased recruitment of P5 3 binding protein 1 (53BP1) to DNA-damage sites, suggesting delayed DNA repair ( Madej-Pilarczyk 2009, Starke 2013). This variant has also been identified in 2/1 11156 of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs150840924). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role in progeroid syndrome and/or dermatological abnormalities when present in homoz ygosity, the clinical significance of this variant is uncertain. In addition, th ere is limited information available to assess if this variant is disease-causin g for cardiomyopathy when present in heterozygosity and therefore the clinical s ignificance of this variant for cardiomyopathy is uncertain.
Invitae	RCV000653929	SCV000775819	pathogenic	Charcot-Marie-Tooth disease type 2	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 435 of the LMNA protein (p.Arg435Cys). This variant is present in population databases (rs150840924, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive progeroid restrictive dermopathy (PMID: 14684700, 19842191, 20662858, 23804595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66802). 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: 23804595, 24623722). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172619	SCV001335682	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001524022	SCV001733779	uncertain significance	Cardiomyopathy	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 435 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant impairs protein interactions (PMID: 24623722) and the recruitment of P53 binding protein to DNA-damage sites indicating delayed DNA repair (PMID: 23804595). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 14684700, 32880476), in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), and in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has also been reported in homozygous state in three infants affected with progeroid syndrome with restrictive dermopathy-like features (PMID: 19842191, 20662858, 23804595). Evaluation of these infants as well as ten heterozygous family members revealed no cardiological abnormalities except for one family member affected with probable age-related hypertensive cardiac disease (PMID: 23804595). A study using a skin sample from one of the infants showed that this variant was associated with decreased lamin A protein and increased DNA double strand breaks (PMID: 23804595). This variant has been identified in 2/250034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in a few individuals affected with autosomal recessive progeroid syndrome, its role in autosomal dominant cardiovascular disorders is not clearly established. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000057265	SCV002503127	likely pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000057265	SCV002549323	likely pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in individuals with DCM or other types of cardiomyopathy (PMID: 14684700, 30847666, 32880476); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest reduced LMNA expression (though not quantified) and impaired cellular interactions (PMID: 19842191, 23804595, 24623722, 30137533, 36301259, 36200863); This variant is associated with the following publications: (PMID: 24846508, 22991222, 26733286, 20662858, 24375749, 24623722, 23804595, 20155465, 23969228, 28663758, 23299917, 25637381, 19842191, 32799420, 32880476, 31383942, 30847666, 33038109, 32376792, 34862408, 30137533, 36301259, 35449878, 36200863, 10939567, 14684700)
Ambry Genetics	RCV002381364	SCV002692510	uncertain significance	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	The p.R435C variant (also known as c.1303C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1303. The arginine at codon 435 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the homozygous state in several probands with autosomal recessive progeria syndrome or restrictive dermopathy (Madej-Pilarczyk A et al. Am. J. Med. Genet. A, 2009 Nov;149A:2387-92; Starke S et al. Aging (Albany NY), 2013 Jun;5:445-59; Youn GJ et al. Clin. Genet., 2010 Aug;78:199-200). It has also been detected in the heterozygous state in cardiomyopathy cohorts and an arrhythmia cohort; however, clinical details were limited in these cases (Vytopil M et al. J. Med. Genet., 2003 Dec;40:e132; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). Functional studies suggest that this variant may impact protein-protein interactions, including BAF binding, and internal structural analysis indicates that this alteration disrupts disrupts the interface of LMNA with BAF (Dittmer TA et al. Mol. Biol. Cell, 2014 May;25:1493-510; Samson C et al. Nucleic Acids Res., 2018 11;46:10460-10473; Ambry internal data). However, the mechanism of pathogenicity for progeria syndrome is not well-established and the clinical significance of this impact is unclear. 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 supporting evidence, this variant is expected to be causative of autosomal recessive Hutchinson-Gilford progeria syndrome when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathies is unclear.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057265	SCV000088378	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148606	SCV000190321	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research
GeneReviews	RCV000150953	SCV000196613	not provided	Hutchinson-Gilford syndrome		no assertion provided	literature only