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

gnomAD frequency: 0.00001  dbSNP: rs58672172

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057255	SCV000234695	uncertain significance	not provided	2020-09-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27841971, 28663758, 18585512, 20160190, 17250669, 30012837, 30488537)
Invitae	RCV000653937	SCV000775827	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-05-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 14519). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 30488537). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. This missense change has been observed in individual(s) with lipodystrophy and dilated cardiomyopathy (PMID: 17250699, 20160190). This variant is present in population databases (rs58672172, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the LMNA protein (p.Arg399Cys).
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174241	SCV001337370	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188431	SCV001355490	uncertain significance	Cardiomyopathy	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 399 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change nuclear morphology or lamin A localization (PMID: 20160190). Another study has shown that this variant causes a moderate defect in lamin A assembly, weakening the interaction between lamin A and NUP155, a key component of nuclear pore complexes, and reducing cardiac sodium channel density (PMID: 30488537). However, clinical relevance of these observations is not known. This variant has been reported in an individual affected with early-onset dilated cardiomyopathy and in his unaffected mother (PMID: 30012837). This proband also carried a pathogenic truncation variant in the TTN gene, which was inherited from his affected father. This variant has also been reported in an individual affected with familial partial lipodystrophy (PMID: 17250669) and in an individual affected with atrial fibrillation (PMID: 30488537). This variant has been identified in 3/248876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002336085	SCV002641456	uncertain significance	Cardiovascular phenotype	2021-12-31	criteria provided, single submitter	clinical testing	The p.R399C variant (also known as c.1195C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1195. The arginine at codon 399 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was originally reported in a patient with familial partial lipodystrophy (Lanktree M et al. Clin Genet. 2007;71(2):183-6). The p.R399C variant was also detected in a proband with severe dilated cardiomyopathy but not in his affected father; however, after subsequent analysis, a TTN A-band truncation was also reported in the proband and the affected father (Parks SB et al. Am Heart J. 2008;156(1):161-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14; Cowan JR et al. Circ Genom Precis Med, 2018 07;11:e002038). In vitro studies using transiently expressed fusion constructs showed nuclear morphology and lamin A localization patterns of p.R399C were comparable with wild-type (Cowan et al 2010); additional functional studies suggested some interference with protein interactions involving NUP155; however, clinical impact was not determined (Han M et al. Hum. Mutat., 2019 03;40:310-325). Another alteration at the same codon, p.R399H (c.1196G>A), was reported in a patient with metabolic laminopathy (Decaudain A et al. J Clin Endocrinol Metab. 2007;92(12):4835-44). This amino acid position is not well conserved in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
OMIM	RCV000015616	SCV000035881	pathogenic	Familial partial lipodystrophy, Dunnigan type	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