Submissions for variant NM_170707.4(LMNA):c.1195C>T (p.Arg399Cys) (rs58672172)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057255	SCV000234695	uncertain significance	not provided	2015-07-07	criteria provided, single submitter	clinical testing	The R399C variant in the LMNA gene has been reported previously in one individual with familial partial lipodystrophy, however no segregation data was reported (Lanktree M et al., 2007). The R399C variant in the LMNA gene has also been identified in one individual with DCM, however testing of additional family members showed that this variant did not co-segregate with disease (Parks S et al., 2008). In addition, functional studies have shown that the R399C mutation shows nuclear morphology similar to wild type (Cowan J et al., 2010). The R399C mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R331Q 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. This substitution occurs at a position that is conserved in mammals. Furthermore, a missense mutation in this residue (R399H) and mutations in nearby residues (S395L, R397C, R401C) have been reported in HGMD in association with cardiomyopathy, metabolic laminopathy and muscular dystrophy (Stenson P et al., 2014), further supporting the functional importance of this residue and region of the protein. Nevertheless, in silico analysisis inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae	RCV000653937	SCV000775827	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 399 of the LMNA protein (p.Arg399Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs58672172, ExAC 0.002%). This variant has been reported in an individual affected with lipodystrophy (PMID: 17250699) This variant has also been reported in an individual affected with dilated cardiomyopathy, however, it did not segregate with disease in this family (PMID: 20160190). ClinVar contains an entry for this variant (Variation ID: 14519). This variant has been reported to affect LMNA protein function (PMID: 30488537). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001174241	SCV001337370	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color	RCV001188431	SCV001355490	uncertain significance	Cardiomyopathy	2019-08-26	criteria provided, single submitter	clinical testing
OMIM	RCV000015616	SCV000035881	pathogenic	Familial partial lipodystrophy 2	2007-02-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057255	SCV000088368	not provided	not provided		no assertion provided	not provided
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257937	SCV001434747	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research