ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1303C>T (p.Arg435Cys) (rs150840924)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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, Partners HealthCare 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 2017-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 435 of the LMNA protein (p.Arg435Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs150840924, ExAC 0.002%). This variant has been reported as homozygous in individuals affected with autosomal recessive progeroid restrictive dermopathy and to segregate with disease in these families (PMID: 19842191, 20662858, 23804595). This variant has been reported as heterozygous in one individual affected with dilated cardiomyopathy, and as heterozygous in several individuals without cardiac disease (PMID: 14684700, 19842191, 20662858, 23804595). ClinVar contains an entry for this variant (Variation ID: 66802). Experimental studies have shown that this missense change results in progressive loss or absence of lamin A levels in-vivo as well as impaired protein interactions (PMID: 23804595, 24623722). For these reasons, this variant has been classified as Pathogenic.
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 pathogenic Hutchinson-Gilford syndrome 2015-01-08 no assertion criteria provided literature only

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