rs59885338
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The ENST00000368300.9(LMNA):c.892C>T(p.Arg298Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R298H) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
LMNA
ENST00000368300.9 missense
ENST00000368300.9 missense
Scores
17
2
1
Clinical Significance
Conservation
PhyloP100: 3.19
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in ENST00000368300.9
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156135269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2159261.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 1-156135268-C-T is Pathogenic according to our data. Variant chr1-156135268-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14498.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=11, Uncertain_significance=4, not_provided=1}. Variant chr1-156135268-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.892C>T | p.Arg298Cys | missense_variant | 5/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.892C>T | p.Arg298Cys | missense_variant | 5/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.892C>T | p.Arg298Cys | missense_variant | 5/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 | |
| LMNA | ENST00000677389.1 | c.892C>T | p.Arg298Cys | missense_variant | 5/10 | NM_005572.4 | ENSP00000503633 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250398Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135628
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461272Hom.: 0 Cov.: 34 AF XY: 0.0000399 AC XY: 29AN XY: 726946
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GnomAD4 genome 0.0000263 AC: 4AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74378
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:15Uncertain:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:6Other:1
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2023 | Published functional studies demonstrate a damaging effect as cells from R298C homozygous knock in mice showed downregulation of LMNA at both the protein and mRNA level (Poitelon et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12467734, 14607793, 11799477, 18549403, 17347251, 17536044, 35383421, 16809772, 10939567, 30340945, 34862408, 35449878, 22331516, 31383942) - |
Charcot-Marie-Tooth disease type 2B1 Pathogenic:5Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 02, 2023 | The observed missense variant c.892C>T(p.Arg298Cys) in LMNA gene has been reported previously in multiple individuals in homozygous and heterozygous state in individuals with Charcot-Marie-Tooth disease (Van Tienen FHJ, et al., 2019, Poitelon Y, et al., 2012). Experimental studies have shown the downregulation of LMNA at both the protein and mRNA level (Poitelon et al., 2012). A different amino acid change p.Arg298Pro as a known pathogenic variant has been reported (Hamadouche T, et al., 2008). The c.892C>T variant has 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretations as Uncertain Significance/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen-probabaly damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Arginine at position 298 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Arg298Cys in LMNA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 18, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Moderate+PM3+PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative and gain of function are associated with missense variants and skeletal muscle involvement while loss of function is associated with protein truncating variants and cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated coil 2 region within the IF rod domain (UniProt). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.R289P and p.R289L variants have been classified as Variants of Uncertain Significance in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with autosomal recessive Charcot-Marie-Tooth disease, type 2 (AR CMT) and has been described as a likely North Western African founder mutation (ClinVar; PMIDs: 11799477, 12467734, 30340945, 18549403). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Fibroblast cells from an individual with AR CMT demonstrated increased apoptotic, but reduced proliferation activity. Moreover, downregulation of LMNA mRNA and corresponding protein levels has been reported in tissues from the homozygous p.R298C knock-in mouse model although a AR CMT clinical phenotype was not found (PMIDs: 17274801, 22331516). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 20, 2022 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 298 of the LMNA protein (p.Arg298Cys). This variant is present in population databases (rs59885338, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14607793, 17347251, 18549403). It is commonly reported in individuals of North African ancestry (PMID: 11799477, 14607793, 17347251, 18549403). ClinVar contains an entry for this variant (Variation ID: 14498). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2022 | The p.R298C pathogenic mutation (also known as c.892C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 892. The arginine at codon 298 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in multiple homozygous individuals with autosomal recessive Charcot-Marie-Tooth disease, has shown segregation with disease in multiple families of Algerian or Moroccan descent, and has been described as a north western African founder mutation (Tazir M et al. Brain, 2004 Jan;127:154-63; Chaouch M et al. Neuromuscul Disord, 2003 Jan;13:60-7; Bouhouche A et al. Brain, 2007 Apr;130:1062-75; Hamadouche T et al. Ann Hum Genet, 2008 Sep;72:590-7). In vitro studies indicate this variant may impact protein function and lead to abnormal nuclear aggregates in some mammalian cell lines (Dreuillet C et al. Biol Cell, 2008 Jan;100:51-61; Anderson CL et al. NPJ Genom Med, 2021 Dec;6:103). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive Charcot-Marie-Tooth disease when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant cardiomyopathy and other laminopathies is unclear. - |
Autosomal recessive axonal hereditary motor and sensory neuropathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 02, 2018 | The p.Arg298Cys variant in LMNA has been reported as homozygous in at least 25 N orth African consanguineous families with clinical features of Charcot Marie Too th Disease variant 2B1 (CMT2B1) and has been described as a founder variant in t his population (De Sandre-Giovannoli 2002, Chaouch 2003, Bouhouche 2007, Ben Yao u 2007, Hamadouche 2008). Animal models of this homozygous variant are associate d with some molecular findings but not the phenotypic abnormalities seen in CMT2 B1 patients (Poitelon 2012). This variant has been identified in 6/1111132 of Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs59885338) and reported in ClinVar (Variation ID# 14498) ; however its frequency is low enough to be consistent with a recessive carrier frequency. In addition, computational prediction tools and conservation analysis suggest that the p.Arg298Cys variant may impact the protein. In summary, this v ariant meets criteria to be classified as pathogenic for CMT2B1 in an autosomal recessive manner based upon segregation studies, low frequency in controls, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2_Supporting; PP3. - |
Hutchinson-Gilford syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Color Diagnostics, LLC DBA Color Health | May 15, 2023 | This missense variant replaces arginine with cysteine at codon 298 of the lamin A/C proteins. 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 is a well-known founder mutation in North African countries and has been reported to segregate with autosomal recessive Charcot-Marie-Tooth type 2 in affected families (PMID: 11799477, 12467734, 14607793, 17347251; Clinvar variation ID: 14498). Cardiac systems were normal in all of over 20 homozygotes assessed (PMID: 12467734, 14607793). Over 40 heterozygous carriers were reported from these families, who were all asymptomatic except for one individual with nonspecific cardiac abnormalities (PMID: 17536044). This variant has also been reported in another two heterozygous individuals referred for cardiac catheterization (PMID: 32792077). This variant has been identified in 9/250398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive Charcot-Marie-Tooth type 2 (ClinVar variation ID:14498). - |
Familial partial lipodystrophy, Dunnigan type Uncertain:1
| Uncertain significance, flagged submission | clinical testing | New York Genome Center | Dec 17, 2020 | The heterozygous c.892C>T (p.Arg298Cys) variant in LMNA is a known pathogenic variant for autosomal recessive Charcot-Marie-Tooth disease, type 2B1(CMT2B1), and has been reported as homozygous in multiple consanguineous families affected with CMT2B1 [PMID: 11799477;PMID: 14607793;PMID: 12467734]. Family-members carrying heterozygous p.Arg298Cys variant were apparently normal [PMID: 11799477;PMID: 14607793;PMID: 12467734]. The variant has been reported in ClinVar database as pathogenic for recessive CMT2B1 disease [Variation ID:14498]. The p.Arg298Cys variant has 0.00002627 allele frequency in the gnomAD(v3) database (4 out of 152,244 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the general population. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools. Given that heterozygous carriers of p.Arg298Cys were apparently normal, and due to the absence of evidence supporting its pathogenicity in heterozygous state, the p.Arg298Cys variant in the LMNA gene is reported as a variant of uncertain significance for autosomal dominant familial partial lipodystrophy. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 30, 2024 | This missense variant replaces arginine with cysteine at codon 298 of the lamin A/C proteins. 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 is a well-known founder mutation in North African countries and has been reported to segregate with autosomal recessive Charcot-Marie-Tooth type 2 in affected families (PMID: 11799477, 12467734, 14607793, 17347251; Clinvar variation ID: 14498). Cardiac systems were normal in all of over 20 homozygotes assessed (PMID: 12467734, 14607793). Over 40 heterozygous carriers were reported from these families, who were all asymptomatic except for one individual with nonspecific cardiac abnormalities (PMID: 17536044). This variant has also been reported in another two heterozygous individuals referred for cardiac catheterization (PMID: 32792077). This variant has been identified in 9/250398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive Charcot-Marie-Tooth type 2 (ClinVar variation ID:14498). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;M;M;M;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
D;.;P;D;.;.;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);Loss of MoRF binding (P = 0.0116);.;.;.;
MVP
MPC
2.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at