ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.585C>G (p.Asn195Lys) (rs28933091)

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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 RCV000211789 SCV000198597 pathogenic Primary dilated cardiomyopathy 2013-05-24 criteria provided, single submitter clinical testing The p.Asn195Lys variant in LMNA has been reported in 1 individual with DCM and r hythm abnormalities and segregated with disease in 8 affected family members (5 individuals with DCM and 3 with rhythm abnormalities; Fatkin 1999). The same va riant resulting from a different DNA change (c.585C>A) has been reported in 1 fa mily with DCM and conduction system disease (5 individuals with DCM and 4 obliga te carriers with SCD; van Tintelen 2007). This variant has not been identified i n large population studies, though it is listed in dbSNP without frequency infor mation (rs28933091). Mice homozygous for this variant exhibited features consist ent with the human phenotype (Mounkes 2005) and other functional studies support that this variant impacts proper protein localization (Ostlund 2001, Raharjo 20 01). In summary, this variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/LMM) based upon segregation studies, abse nce from controls, and functional evidence.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000057425 SCV000885656 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing The LMNA c.585C>G, p.Asn195Lys variant (rs28933091) has been reported in multiple individuals with conduction system disease and dilated cardiomyopathy, segregating with the disorder (Fatkin 1999). Functional characterization of variant protein in cell lines indicates impaired in vitro assembly of the lamina network (Zwerger 2013), reduced nuclear translocation of cardiac transcription factor (Ho 2013), altered actin dynamics (Ho 2013), loss of Emerin in the nuclear envelope (Ostlund 2001), and formation of large nuclear aggregates (Ostlund 2001, Raharjo 2001). Mice homozygous for this variant suffer from conduction defect and early lethality, with altered expression of genes involved in cardiac development (Mounkes 2005). The variant is listed as pathogenic in ClinVar (Variation ID: 14483), and not observed in the general population databases. The asparagine at residue 195 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. REFERENCES Fatkin D et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 1999 Dec 2;341(23):1715-24. Ho CY et al. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature. 2013 May 23;497(7450):507-11. Mounkes LC et al. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet. 2005 Aug 1;14(15):2167-80 Ostlund C et al. Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. J Cell Sci. 2001 Dec;114(Pt 24):4435-45. Raharjo WH et al. Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. J Cell Sci. 2001 Dec;114(Pt 24):4447-57. Zwerger M et al. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum Mol Genet. 2013 Jun 15;22(12):2335-49.
Invitae RCV000794743 SCV000934169 pathogenic Charcot-Marie-Tooth disease, type 2 2019-07-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 195 of the LMNA protein (p.Asn195Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed to segregate with LMNA-related dilated cardiomyopathy in families (PMID: 10580070, 18035086). ClinVar contains an entry for this variant (Variation ID: 14483). Experimental studies with multiple cell lines and animal models have shown that this missense change disrupts protein localization with accumulation of large intranuclear foci, causes visible defects in lamin A assembly and affects emerin capture (PMID: 11792809, 23427149, 21173262, 12783988, 11792810). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015572 SCV000035837 pathogenic Dilated cardiomyopathy 1A 2013-05-23 no assertion criteria provided literature only
GeneReviews RCV000015572 SCV000041603 pathologic Dilated cardiomyopathy 1A 2011-04-05 no assertion criteria provided curation Converted during submission to Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057425 SCV000088539 not provided not provided no assertion provided not provided

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