ClinVar Miner

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

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Total submissions: 7
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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

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