1-156136335-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_170707.4(LMNA):c.1279C>T(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427G) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1279C>T | p.Arg427Cys | missense_variant | Exon 7 of 12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.1279C>T | p.Arg427Cys | missense_variant | Exon 7 of 10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1279C>T | p.Arg427Cys | missense_variant | Exon 7 of 12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.1279C>T | p.Arg427Cys | missense_variant | Exon 7 of 10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250794Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135674
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1459970Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 726302
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1A Pathogenic:1Uncertain:1
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (Decipher, ClinVar, PMID: 17377071). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (PMID: 17377071). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. However, an alternative change to histidine has been reported as VUS in two studies (PMID: 30847666). (N) 0804 - Variant is present in the population and has previously been described as variant of uncertain significance in two independent cases (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
not provided Uncertain:2
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Previously reported in a 3 week old male who had sudden unexplained infant death (Heathfield et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31383942, 28663758, 10939567, Heathfield2021[Case Report]) -
not specified Uncertain:1
Variant summary: LMNA c.1279C>T (p.Arg427Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251684 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1279C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, sudden unexpected death in infants, atrioventricular and left bundle branch block, chronic kidney disease or steroid-sensitive nephrotic syndrome (Walsh_2017, Park_2019, Heathfield_2021, Pessente_2022, Isaranuwatchai_2022). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28663758, 36267857, 36646731, 35772917, 31383942, 35449878, 28082330, 29773157). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiomyopathy Uncertain:1
This missense variant replaces arginine with cysteine at codon 427 of the lamin A/C protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one infant affected with sudden death (PMID: 36267857), and in one family affected with hypertrophic cardiomyopathy (PMID: 37246508). This variant has been identified in 7/282184 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. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 427 of the LMNA protein (p.Arg427Cys). This variant is present in population databases (rs373584456, gnomAD 0.01%). This missense change has been observed in individual(s) with LMNA-related conditions (PMID: 36267857). ClinVar contains an entry for this variant (Variation ID: 200943). 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. -
LMNA-related disorder Uncertain:1
The LMNA c.1279C>T variant is predicted to result in the amino acid substitution p.Arg427Cys. This variant has been reported in individuals with renal disease (Table S4A, Park et al. 2020. PubMed ID: 31383942; Table S4, Isaranuwatchai et al. 2023. PubMed ID: 36646731) and in an individual that experienced sudden unexplained death in infancy (Heathfield et al. 2021. PubMed ID: 36267857). However, this variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD, which is higher than expected for a pathogenic variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Primary dilated cardiomyopathy Uncertain:1
This missense variant replaces arginine with cysteine at codon 427 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 been identified in 7/282184 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. -
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2;C5979868:Dilated cardiomyopathy 1A Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R427C variant (also known as c.1279C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1279. The arginine at codon 427 is replaced by cysteine, an amino acid with highly dissimilar properties. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at