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

dbSNP: rs28933091

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2021-10-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 11792809, 11792810, 12783988, 21173262, 23427149). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14483). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 10580070, 18035086). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, a(n) neutral and polar amino acid, with lysine, a(n) basic and polar amino acid, at codon 195 of the LMNA protein (p.Asn195Lys).
OMIM	RCV000015572	SCV000035837	pathogenic	Dilated cardiomyopathy 1A	2013-05-23	no assertion criteria provided	literature only
GeneReviews	RCV000015572	SCV000041603	not provided	Dilated cardiomyopathy 1A		no assertion provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057425	SCV000088539	not provided	not provided		no assertion provided	not provided