Submissions for variant NM_170707.4(LMNA):c.1184C>T (p.Ser395Leu)

gnomAD frequency: 0.00001  dbSNP: rs267607561

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001056678	SCV001221132	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 395 of the LMNA protein (p.Ser395Leu). This variant is present in population databases (rs267607561, gnomAD 0.004%). This missense change has been observed in individual(s) with a laminopathy (PMID: 17711925). ClinVar contains an entry for this variant (Variation ID: 66792). 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) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. 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.
GeneDx	RCV000057253	SCV001800970	uncertain significance	not provided	2019-03-19	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in patient with peripheral neuropathy in published literature (Decaudain et al., 2007); Observed in an individual referred for genetic testing at GeneDx who had a different genetic etiology for the phenotype; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28679633, 17711925)
Ambry Genetics	RCV002336206	SCV002635720	uncertain significance	Cardiovascular phenotype	2019-09-17	criteria provided, single submitter	clinical testing	The p.S395L variant (also known as c.1184C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1184. The serine at codon 395 is replaced by leucine, an amino acid with dissimilar properties. This variant was observed in one 60 year old patient with metabolic syndrome, coronary heart disease, atherosclerois, hypertension, insulin-resistant diabetes and related complications including retinopathy, nephropathy, and peripheral neuropathy. However, he lacked clinical lipodystrophy and any muscular symptoms (Decaudain A et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4835-44). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483088	SCV002793096	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2022-03-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996499	SCV004816147	uncertain significance	Primary dilated cardiomyopathy	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 395 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In vitro functional studies suggest that this variant may not have significant impact on LMNA protein binding activity (PMID: 24623722). This variant has been reported in an individual affected with a peripheral neuropathy phenotype (PMID: 17711925). This variant has been identified in 4/279930 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.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057253	SCV000088366	not provided	not provided		no assertion provided	not provided
Blueprint Genetics	RCV000157294	SCV000207026	uncertain significance	Collapse (finding); Family history of sudden cardiac death	2014-02-12	no assertion criteria provided	clinical testing