ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1256G>A (p.Arg419His)

gnomAD frequency: 0.00003  dbSNP: rs777648901
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549013 SCV000657797 uncertain significance Charcot-Marie-Tooth disease type 2 2023-09-22 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 419 of the LMNA protein (p.Arg419His). This variant is present in population databases (rs777648901, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 27650965, 31383942). ClinVar contains an entry for this variant (Variation ID: 476822). 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. 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 RCV001172620 SCV001335683 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Ambry Genetics RCV002420529 SCV002677095 uncertain significance Cardiovascular phenotype 2023-08-03 criteria provided, single submitter clinical testing The p.R419H variant (also known as c.1256G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1256. The arginine at codon 419 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a sudden unexplained death case, a case with suspected Charcot-Marie-Tooth disease, and in individuals reported to have cardiomyopathy and/or cardiac conduction disease; however, clinical details were limited (Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Park J et al. Genet Med. 2020 Jan;22(1):102-111; Volodarsky M et al. J Med Genet. 2021 Apr;58(4):284-288). This amino acid position is highly 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 RCV002483493 SCV002793666 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 2022-01-03 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999467 SCV004821990 uncertain significance Primary dilated cardiomyopathy 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 419 of the LMNA 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 a case of sudden unexplained death (PMID: 27650965). This variant has been reported in an individual with affected with cardiomyopathy and in individuals affected with conduction defects (PMID: 31383942). This variant has also been reported in multiple individuals with no cardiac phenotype (PMID: 28663758, 31383942). This variant has been identified in 14/281984 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.