ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys) (rs142000963)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000057374 SCV000051400 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041340 SCV000065033 likely benign not specified 2017-08-06 criteria provided, single submitter clinical testing The p.Arg644Cys variant in LMNA has been detected by our laboratory in 7 individ uals with cardiomyopathy (2 with DCM, 1 with LVNC, 2 with HCM, 1 with an unspeci fied cardiomyopathy, and 1 with VFib and a T-wave inversion). Four of these pati ents had a very early age at onset (range birth to 7 years) and no family histor y, which is atypical for LMNA variants. The p.Arg644Cys variant has also been id entified in a large number of individuals (>20) with a diverse range of clinical features consistent with laminopathy, isolated cardiomyopathy (DCM, ARVC, HCM) or Hallermann-Streiff syndrome, a rare genetic disorder with clinical overlap wi th some laminopathies (Speckman 2000, Genschel 2001, Csoka 2004, Mercuri 2005, M untoni 2006, Rankin 2008, Pasotti 2008, Perrot 2009, M?ller 2009, Larsen 2011, K ortum 2011, Scharner 2011, Quarta 2012, Vasli 2012, Hoyer 2014). In addition, on e study reported non-segregation with disease in 2 families (Mercuri 2005). This variant has also been identified in 0.2% (106/63724) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs14200 0963) and in gnomAD at 0.2% (242 alleles). Computational prediction tools and co nservation analyses do not provide strong support for or against an impact to th e protein; however, in vitro functional studies indicate the variant may affect nuclear morphology (Csoka 2004). In summary, the lack of segregation with diseas e, its population frequency, and the wide-spectrum of observed phenotypes reduce s the likelihood that the p.Arg644Cys variant can cause disease when present in isolation.
GeneDx RCV000041340 SCV000234713 uncertain significance not specified 2017-08-25 criteria provided, single submitter clinical testing The R644C variant of uncertain significance in the LMNA gene has been reported multiple times in association with LMNA-related disorders, and demonstrates a wide phenotypic spectrum, variable severity, incomplete penetrance, and non-segregation (Genschel et al., 2001; Csoka et al., 2004; Mercuri et al., 2005; Muntoni et al., 2006; Rankin et al., 2008; Pasotti et al., 2008; Moller et al., 2009; Perrot et al., 2009; Scharner et al., 2011; Quarta et al., 2012; Vasli et al., 2012; Larsen et al., 2012; Hoyer et al., 2014; Cann et al., 2016). The R644C variant has been identified in individuals with isolated cardiomyopathy, laminopathies, Hallermann-Streiff syndrome, or Hutchinson-Gilford progeria syndrome, and also in asymptomatic relatives. Additionally, two studies reported that the R644C variant did not segregate with disease in two unrelated families (Mercuri et al., 2005; Muntoni et al., 2006). The Exome Aggregation Consortium (ExAC) reports R644C was observed in 106/63,724 alleles from individuals of Non-Finnish European and 27/16,410 alleles from individuals of South Asian ancestry, including one homozygote, indicating it may be a rare benign variant in these populations (Lek et al., 2016). It has been suggested that the extreme phenotypic variability caused by this pleiotropic LMNA variant could be due to either an altered methylation pattern or abnormal post-translational processing of prelamin A because R644C is located at the C-terminal end of lamin A/C close to the endoproteolytic cleavage site (Perrot et al., 2009; Capell et al., 2006). The R644C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics RCV000245284 SCV000319734 uncertain significance Cardiovascular phenotype 2019-03-19 criteria provided, single submitter clinical testing Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000041340 SCV000332002 likely benign not specified 2016-01-26 criteria provided, single submitter clinical testing
Invitae RCV001084244 SCV000559827 likely benign Charcot-Marie-Tooth disease, type 2 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000041340 SCV000699968 likely benign not specified 2019-03-25 criteria provided, single submitter clinical testing Variant summary: LMNA c.1930C>T (p.Arg644Cys) results in a non-conservative amino acid change located in the Lamin A tail of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 275458 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In the literature, this variant is reported to be associated with pleiotropic disease phenotypes ranging from atypical progeria, lipodystrophy, motor neuropathy, limb girdle muscle weakness and dilated cardiomyopathy. We ascertained literature reporting this variant in multiple patients with a variety of phenotypes, including lipodystrophy, diabetes, distal motor neuropathy, DCM, scoliosis, hepatic steatosis, and limb girdle muscular dystrophy. Many unaffected relatives of these patients also carry the variant of interest, suggesting this variant has "possibly" low penetrance or is not associated with phenotype (Cann_2017, Genschel_2000, Rankin_2008, Muntoni_2006, Vasli_2012, Stehlikova_2017 and Seidelmann_2017). However, its identification as an incidental carryover of testing given its high control frequency cannot be ruled out. Arg644 is located close to ZMPSTE24 cleavage site (codon 646-647) and one study showed that R644C causes a "partial cleavage" defect by ZMPSTE24, thereby impacting the proteolytic maturation of the nuclear precursor protein of lamin A (Barrowman_2012). Another functional study showed that although this variant did not significantly affect the levels of nuclear abnormalities, it did result in a potential loss of cellular compartmentalization as evidenced by a significant increase in non-lethal ruptures of the nuclear envelope relative to the wild-type LMNA protein (De Vos_2011). However, the results and conclusions drawn from this study are not directly correlated to the mechanisms and presentation of disease associated with Laminopathies attributed to LMNA variants. In addition, multiple clinical diagnostic laboratories/reputable databases provided conflicting classifications including likely pathogenic (n=1), VUS (n=7), and likely benign (n=4). Taken together, as the possibility of its involvement with another low penetrance laminopathy phenotype cannot be entirely ruled out, this variant is classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000041340 SCV000747924 uncertain significance not specified 2017-03-31 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755679 SCV000883087 uncertain significance Dilated cardiomyopathy 1A 2018-11-21 criteria provided, single submitter clinical testing
Color RCV000771143 SCV000902953 likely benign Cardiomyopathy 2018-03-16 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000057374 SCV001144440 benign not provided 2019-01-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000057374 SCV001147469 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000144868 SCV001337374 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001174411 SCV001337549 benign Monogenic diabetes 2018-11-02 criteria provided, single submitter research ACMG criteria: BS4 (lack of segregation in 15770669, 16585054), BS1 (0.2% MAF in EurNF), BS2 (two homozygotes in gnomAD), PS3 (reduces cleavage efficacy of prelaminA tail: 28663758, 22355414) [REVEL 0.608, PP3 (8), BP4 (2) = conflicting evidence, not using] = Benign
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197206 SCV001367843 uncertain significance CNS disorder 2019-05-09 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197509 SCV001368280 uncertain significance Hypertrophic cardiomyopathy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198415 SCV001369349 uncertain significance Muscle weakness; Generalized hypotonia; Craniosynostosis; Skeletal muscle atrophy; Gowers sign 2020-03-20 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP2,PP3,PS4_MOD. This variant was detected in heterozygous state.
OMIM RCV000015626 SCV000035891 uncertain significance Variant of unknown significance 2009-11-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057374 SCV000088487 not provided not provided no assertion provided not provided
Dept. of Medical Genetics, Telemark Hospital Trust RCV000144868 SCV000172139 likely pathogenic Charcot-Marie-Tooth disease 2013-11-01 no assertion criteria provided research Observed in two induviduals from two different families.
CSER _CC_NCGL, University of Washington RCV000148602 SCV000190317 uncertain significance Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000057374 SCV000925150 uncertain significance not provided 2017-01-03 no assertion criteria provided provider interpretation

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