ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1621C>T (p.Arg541Cys) (rs56984562)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211786 SCV000065018 pathogenic Primary dilated cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing The p.Arg541Cys variant in LMNA has been identified in 6 individuals with DCM (F orissier 2003, Muchir 2004, Saj 2009, LMM data) and in one individual with sudde n cardiac death (Hookana 2008), occurring de novo in 2 cases (paternity confirme d). It was also shown to segregate with disease in 5 affected relatives from 4 f amilies (Forissier 2003, Hookana 2008, LMM data). It was absent from large popul ation studies. This variant has been shown to cause nuclear lamina abnormalities (Muchir 2004). Computational prediction tools and conservation analysis suggest that this variant may impact the protein and additional variants involving this amino acid, p.Arg541Ser and p.Arg541His, have been associated with DCM. In summ ary, this variant meets our criteria to be classified as pathogenic based upon c ase observations, de novo occurrences, segregation studies, absence from control s, and functional evidence. ACMG/AMP Criteria applied: PM6_Strong; PM2; PM5; PS4 _Moderate; PP1_Moderate; PP3.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057343 SCV000224965 pathogenic not provided 2014-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000057343 SCV000234708 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The R541C variant in the LMNA gene has been reported in association with DCM and/or arrhythmia (Forissier J et al., 2003; Muchir A et al., 2004; Saj M et al., 2010; Pugh et al., 2014). Forissier et al. identified R541C in a father and daughter diagnosed with dilated cardiomyopathy, each with a history of arrhythmias. R541C occurred de novo in the first individual diagnosed in this family, explaining the lack of a family history significant for cardiomyopathy or arrhythmia. In a study by Pugh et al., R541C was identified in two individuals with dilated cardiomyopathy, one of which also carried a variant in the LDB3 gene. Muchir et al. examined the effect of R541C on the nuclear envelope in cultured skin fibroblasts and reported an absence or significant decrease in lamin B1 expression, as well as a lobulated nuclear envelope, in comparison to controls. R541C results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral Cysteine at a residue that is highly conserved across species. Moreover, other variants at the same codon (R541H, R541G, R541P, R541S) have been reported in association with dilated cardiomyopathy and muscular dystrophy, further supporting the functional importance of this position of the protein. The R541C variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R541C in the LMNA gene is interpreted as a disease-causing variant
Athena Diagnostics Inc RCV000041325 SCV000255784 pathogenic Dilated cardiomyopathy 1A 2015-08-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242991 SCV000320572 pathogenic Cardiovascular phenotype 2018-08-20 criteria provided, single submitter clinical testing Confirmed de novo alteration in individual with classic disease.;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function by in vitro/ex vivo assay;Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position
Invitae RCV000462793 SCV000548875 pathogenic Charcot-Marie-Tooth disease, type 2 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 541 of the LMNA protein (p.Arg541Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. While this variant is present in population databases (rs56984562), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 14675861, 22464770, 27532257, 24503780) and a family with cardiac arrest and left ventricular fibrosis (PMID: 18031519). This variant has been shown to arise de novo in individuals affected with dilated cardiomyopathy (PMID: 14675861, 18031519), and to segregate with the disease in one family (PMID: 15724423). ClinVar contains an entry for this variant (Variation ID: 48046). Five different missense substitution at this codon (p.Arg541Pro, p.Arg541Cys, p.Arg541Ser, p.Arg541Gly, p.Arg541Lys) are reported to be deleterious (PMID: 24623722, 22186027). This indicates that the arginine residue is important for LMNA protein function. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000041325 SCV000803622 likely pathogenic Dilated cardiomyopathy 1A 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Dilated cardiomyopathy, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PMID:18035086,16061563,18564364,21085127). PS3 => Well-established functional studies show a deleterious effect (PMID:15372542).
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057343 SCV000088456 not provided not provided no assertion provided not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000057343 SCV000925146 pathogenic not provided 2016-06-06 no assertion criteria provided provider interpretation We consider this variant to be very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The reasons for this classification include strong case data, including de novo occurrence and some segregation data in two families; functional studies supporting pathogenicity; and multiple other reported disease causing variants affecting the same codon. We have seen this variant in a patient with DCM. Testing was performed by Invitae. The variant has been seen in at least 6 unrelated cases of dilated cardiomyopathy and/or arrhythmia (not including this patient's family). Forissier J et al., 2003 reported the R541C variant in a father and daughter with DCM and arrhythmias. R541C occurred de novo in the father in the context of a negative family history in preceding generations. Muchir et al., 2004 reported to be a 29 year-old with DCM and conduction system disease. They performed functional studied in cultured skin fibroblasts and reported an absence or significant decrease in lamin B1 expression and a lobulated nuclear envelope with the R541C variant compared to controls. Hookana et al., 2008 reported the R541C variant in a mother with a history of an aborted SCD and LV hypokinesia and thinning and daughter who died suddenly and was found to have localize LV thinning and fibrosis. The variant was found to have occurred de novo in the mother in the context of a negative family history. Saj M et al., 2010 reported a 19 year old with LV DCM s/p ICD implantation and aborted VFib cardiac arrests, with a family history of SCD. Pugh et al., 2014 reported R541C in two individuals with DCM, one of which also carried a mutation in the LDB3 gene, per the LMM ClinVar entry. Other variants at the same codon (R541H, R541G, R541P, R541S) have been reported in association with dilated cardiomyopathy and other laminopathies, supporting the hypothesis that this codon occurs at a functionally important location in the protein. Per the Invitae report, "This sequence change replaces arginine with cysteine at codon 541 of the LMNA protein (p.Arg541Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine." Please note that the average coverage at this site in ExAC is poor: The mean depth is ~16x, the median depth is 4x, and ~95% of people have ~1x coverage, with ~40% having 5x coverage. The variant was reported online in 2 of 10,695 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). Specifically, the variant was observed in 2 of 4,568 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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