Submissions for variant NM_170707.4(LMNA):c.1363C>T (p.Arg455Cys)

gnomAD frequency: 0.00001  dbSNP: rs397517892

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041316	SCV000065008	uncertain significance	not specified	2013-03-06	criteria provided, single submitter	clinical testing	The Arg455Cys variant in LMNA has not been reported in any individuals with card iomyopathy, but has been reported in one female with polycystic ovary syndrome a nd was absent from >1000 control chromosomes (Urbanek 2009). Additionally, a dif ferent variant at the same position (Arg455Pro) has been reported as de novo in a child with congenital muscular dystrophy (Quijano-Roy 2008). The Arg455Cys var iant has not been previously identified by our laboratory nor identified in larg e and broad European American and African American populations by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/), though it may be commo n in other populations. Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg455Cys vari ant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, additional studies are needed to fully asse ss the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052345	SCV001216552	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 455 of the LMNA protein (p.Arg455Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 48038). 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%. This variant disrupts the p.Arg455 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18551513; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001526075	SCV001736351	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 455 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 2/201336 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.
Fulgent Genetics, Fulgent Genetics	RCV002490578	SCV002776900	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	2021-09-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996454	SCV004814495	uncertain significance	Primary dilated cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 455 of the lamin A/C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with polycystic ovary syndrome (PMID: 19401371). This variant has been identified in 2/201336 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.