ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.646C>T (p.Arg216Cys) (rs794728591)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000241819 SCV000317486 uncertain significance Cardiovascular phenotype 2012-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Blueprint Genetics RCV000208531 SCV000264008 likely pathogenic Primary dilated cardiomyopathy 2015-03-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725540 SCV000337604 uncertain significance not provided 2015-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000725540 SCV000234677 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The R216C likely pathogenic variant in the LMNA gene was originally reported in one individual who had either clinical or familial evidence of a laminopathy, though specific details were not provided (van Riksingen et al., 2013). Subsequently, Al-Saaidi et al. (2018) demonstrated that R216C segregated with variable laminopathy phenotypes in many affected individuals from a single large family. Protein expression studies revealed that R216C variant carriers had a mutant protein to wild-type protein ratio of 30:70, supporting that R216C is associated with a later disease onset and more favorable prognosis compared to other pathogenic LMNA variants (Al-Saaidi et al., 2018). The R216C variant has been identified in conjunction with additional cardiogenetic variants in multiple unrelated individuals referred for genetic testing at GeneDx; however, segregation data is currently limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. R216C is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R216C 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. Moreover, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Finally, multiple missense variants in nearby residues (L215P, L215V, K219N, K219T, R220C, R220G) have been reported in the Human Gene Mutation Database in association with cardiac or neuromuscular phenotypes (Stenson et al., 2014).In summary, R216C in the LMNA gene is interpreted as a likely pathogenic variant.
Invitae RCV000528116 SCV000657818 pathogenic Charcot-Marie-Tooth disease, type 2 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 216 of the LMNA protein (p.Arg216Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with conduction disease and/or dilated cardiomyopathy (PMID: 23183350, 29237675, 27506821, 28878402, 29943882, 30007954). This variant has also been observed to segregate with conduction disease and cardiomyopathy in a family (PMID: 29943882). ClinVar contains an entry for this variant (Variation ID: 200938). Experimental studies have shown that this missense change impairs Lamin A/C localization in the nuclear membrane (PMID: 28878402). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000182360 SCV000731751 likely pathogenic Primary dilated cardiomyopathy; Laminopathy 2018-06-29 criteria provided, single submitter clinical testing The p.Arg216Cys variant in LMNA has been reported at least 10 individuals with c ardiomyopathy or other features suggestive of a laminopathy (Al-Saaidi 2018, van Rijsingen 2013, Ambry pers. comm., BluePrint pers. comm, EGL pers. comm., GeneD x pers. comm., Invitae pers. comm., Stanford pers. comm., LMM data) and segregat ed with disease in 18 affected individuals from one large family with DCM (Al-Sa aidi 2018). It has also been identified in 2/277170 chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org) and has been repor ted in ClinVar (Variation ID:200938). Computational prediction tools and conserv ation analysis suggest that the p.Arg216Cys variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Arg216Cys variant is likely pathogenic. ACMG/AMP Criteria appl ied: PP1_Strong, PS4_Moderate, PM2, PP3.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000725540 SCV000925149 uncertain significance not provided 2017-08-17 no assertion criteria provided provider interpretation p.Arg216Cys (R216C; c.646C>T) in exon 4 of the LMNA gene (NM_005572.3) Given the suspicious case data and rarity in the general population, we consider this variant a variant of uncertain significance, likely pathogenic. At this time, we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, if the patient is able to get her family involved for segregation analysis and it segregates with disease, this variant is a good candidate for pathogenicity. The variant has been seen in at least 13 unrelated cases of cardiomyopathy (not including this patient's family). Most of these patients were seen at other genetic testing labs. Some of these patients have conduction system disease and a family history of sudden cardiac death. The case data is strong; however, segregation and functional data is lacking in any of these families, which leads us to a classification of VUS-likely pathogenic. We have seen this variant in 3 of our patients - one with cardiomyopathy, family history of sudden cardiac death/arrest, conduction system disease, arrhythmias, another with severe dilated cardiomyopathy and a family history of DCM, and another with recurrent VT and family history of VT/SVT and older-onset cardiomyopathy. This variant has been reported in one patient who is part of a multicenter cohort of 269 LMNA-positive individuals recruited in Europe with clinical or family evidence of laminopathy (van Rijsingen I et al., 2013). Ancestry is not provided. Subjects were recruited in Denmark, France, Germany, Italy, Netherlands, UK. The variant was also report in a paper on ablation for laminopathy, however the case amy be redundant with that reported by van Rijsingen et al given overlap in authors and recruitment sites and lack of details to assess potential redundancy. The variant is listed in an LMNA database online, but I can't open the variant's listing (http://www.umd.be/LMNA/W_glossary/Glossary_80C7.shtml). Ito et al (2017) included this variant in some analyses in their paper on impact of LMNA variants on splicing, however it appears it was only evaluated with an in silico algorithm and was not studied further. This is a non-conservative amino acid change, resulting in the replacement of a basic Arginine with a polar Cysteine that is capable of forming disulfide bridges. The Arginine at this location is very highly conserved across vertebrate species (it is an Asparagine in one species of bird and a Histidine in lamprey). Variants in nearby residues (F206L, I210S, L215P, L215V, K219N, K219T, H222P, H222Y, E223K, R225Q, L226V) have been reported in HGMD in association with dilated cardiomyopathy and/or muscular dystrophy, further supporting the functional importance of this region of the protein. According to the Ambry report, in silico analysis with PolyPhen predicts the variant to be “Probably Damaging” with a score of 0.97 and SIFT predicts it to be “Deleterious” with a score of (0.01). Its Grantham score is 180. According to the Invitae report, SIFT, PolyPhen-2, and Align-GVGD all suggest the variant is disruptive. The variant was reported online in 2 of 138585 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 10152 individuals of Ashkenazi Jewish descent (MAF=0.009850%) and 1 of 15391 South Asians (MAF=0.003249%). 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. There is one individual of “Other” ancestry with a different variant at the same codon: p.Arg216His.

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