ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1262T>C (p.Leu421Pro)

gnomAD frequency: 0.00001  dbSNP: rs267607564
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000694118 SCV000822547 uncertain significance Charcot-Marie-Tooth disease type 2 2022-08-09 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects LMNA function (PMID: 17612587, 23977161, 24943589). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 66798). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 17711925, 32376792). This variant is present in population databases (rs267607564, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 421 of the LMNA protein (p.Leu421Pro). 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 RCV000772169 SCV000905286 uncertain significance Cardiomyopathy 2023-01-19 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 421 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant causes accumulation of prelamin A and nuclear shape abnormalities (PMID: 17612587) and impacts the interaction with nesprin-2 (PMID: 23977161). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with severe metabolic syndrome (PMID: 17711925), in an individual with laminopathy with musculoskeletal and metabolic phenotype (PMID: 23853504), in an individual with laminopathy with cardiac and metabolic phenotype (PMID: 23853504), and in an individual with suspected Charcot-Marie-Tooth (PMID: 32376792). This variant has been identified in 3/282158 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.
GeneDx RCV000057261 SCV002072679 likely pathogenic not provided 2023-02-23 criteria provided, single submitter clinical testing Identified in a patient with obesity, diabetes, hypertension, left ventricular hypertrophy, and muscle pain and weakness in published literature (Decaudain et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional assays have contradictory findings on the effect of p.(L421P) on lamin A nucleus import in cell lines (Yang et al., 2013; Kiel et al., 2014), and suggest impairment of morphological and physiological features in patient cells, although quantitative analysis of lamin A expression was not described (Caron et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23977161, 24943589, 17711925, 32376792, 23853504, 17612587, 36354755, 10939567)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281901 SCV002572466 uncertain significance not specified 2022-08-03 criteria provided, single submitter clinical testing Variant summary: LMNA c.1262T>C (p.Leu421Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250794 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1262T>C has been reported in the literature in individuals with LMNA-Related Disorders (examples: Caron_2007, Decaudain_2007, Carboni_2013, Lin_2020, and Volodarsky_2021). However, these reports do not provide unequivocal conclusions about association of the variant with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant had nuclear shape abnormalities, reduced proliferative activity, increased mitochondrial alterations, increased oxidative stress and premature cellular senescence (Caron_2007). Additional studies reported the variant does not impair trafficking of the protein (Decaudain_2007) and does not alter distribution of Nesprin-2 but shows reduced Nesprin-2 binding (Yang_2013). Furthermore, Kiel et al (2014) determined the variant has significantly reduced nuclear accumulation and exhibits altered subcellular localization and reduced lamina incorporation. However, this data does not allow convincing conclusions about the variant effect and how it relates to onset of laminopathies clinically. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical importance becomes available.
Ambry Genetics RCV002444514 SCV002680619 uncertain significance Cardiovascular phenotype 2017-03-21 criteria provided, single submitter clinical testing The p.L421P variant (also known as c.1262T>C), located in coding exon 7 of the LMNA gene, results from a T to C substitution at nucleotide position 1262. The leucine at codon 421 is replaced by proline, an amino acid with similar properties. This alteration was detected in an individual from a metabolic syndrome cohort with central obesity, diabetes, hypertension and left ventricular hypertrophy (Decaudain A et al. J Clin Endocrinol Metab. 2007;92:4835-44). Limited functional studies have suggested this variant may result in mild defects in lamin A intranuclear localization (Decaudain A et al. J Clin Endocrinol Metab. 2007;92:4835-44; Yang L et al. PLoS ONE. 2013;8:e71850; Kiel T et al. Int J Biochem Cell Biol. 2014;53:271-80). This amino acid position is not 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.
Revvity Omics, Revvity Omics RCV000057261 SCV003814683 uncertain significance not provided 2021-11-29 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057261 SCV000088374 not provided not provided no assertion provided not provided

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