ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1364G>A (p.Arg455His)

gnomAD frequency: 0.00001  dbSNP: rs267607597
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001190369 SCV001357832 uncertain significance Cardiomyopathy 2020-01-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 455 of the LMNA protein. 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.
Invitae RCV001350407 SCV001544806 uncertain significance Charcot-Marie-Tooth disease type 2 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 455 of the LMNA protein (p.Arg455His). This variant is not present in population databases (gnomAD no frequency). 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: 927247). 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.
Ambry Genetics RCV002379734 SCV002702140 uncertain significance Cardiovascular phenotype 2019-09-20 criteria provided, single submitter clinical testing The p.R455H variant (also known as c.1364G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1364. The arginine at codon 455 is replaced by histidine, an amino acid with highly similar properties. A different variant affecting this codon (p.R455P, c.1364G>C) has been reported in an individual with congenital muscular dystrophy (Quijano-Roy S et al. Ann. Neurol., 2008 Aug;64:177-86). This amino acid position is highly conserved through mammals but not 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 alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002480633 SCV002781886 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; 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 2021-10-20 criteria provided, single submitter clinical testing

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