rs374726751
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP5_Strong
The NM_170707.4(LMNA):c.1189C>T(p.Arg397Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,902 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R397H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 1 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
3
10
7
Clinical Significance
Conservation
PhyloP100: 1.84
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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.
PP5
Variant 1-156136245-C-T is Pathogenic according to our data. Variant chr1-156136245-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 211387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=7}. Variant chr1-156136245-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1189C>T | p.Arg397Cys | missense_variant | 7/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.1189C>T | p.Arg397Cys | missense_variant | 7/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1189C>T | p.Arg397Cys | missense_variant | 7/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.1189C>T | p.Arg397Cys | missense_variant | 7/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248570Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134560
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1459668Hom.: 1 Cov.: 34 AF XY: 0.0000262 AC XY: 19AN XY: 726176
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GnomAD4 genome 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:3Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 28, 2016 | - - |
| Likely pathogenic, flagged submission | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely pathogenic, flagged submission | clinical testing | Blueprint Genetics | Jul 17, 2018 | - - |
| Likely pathogenic, flagged submission | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 19, 2018 | Variant summary: LMNA c.1189C>T (p.Arg397Cys) 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 2.5e-05 in 275346 control chromosomes. This frequency is lower than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (2.5e-05 vs 0.0001), allowing no conclusion about variant significance. The c.1189C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and laminopathy. These reports do not provide unequivocal conclusions about an association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 20, 2015 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 29, 2023 | This missense variant replaces arginine with cysteine at codon 397 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 23062543, 30847666). It has also been reported in an individual affected with atrial septal aneurysm and atrioventricular block (PMID: 28254188), in an individual affected with cardiomyopathy and conduction defects (PMID: 31383942), and in an individual affected with unspecified cardiac disease (PMID: 23183350). This variant has been identified in 7/279952 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 397 of the LMNA protein (p.Arg397Cys). This variant is present in population databases (rs374726751, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomopathy (DCM) or unspecified cardiac disease (PMID: 23062543, 23183350, 30847666). ClinVar contains an entry for this variant (Variation ID: 211387). 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. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with cysteine at codon 397 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 23062543, 30847666). It has also been reported in an individual affected with atrial septal aneurysm and atrioventricular block (PMID: 28254188), in an individual affected with cardiomyopathy and conduction defects (PMID: 31383942), and in an individual affected with unspecified cardiac disease (PMID: 23183350). This variant has been identified in 7/279952 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2021 | The p.R397C variant (also known as c.1189C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1189. The arginine at codon 397 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in an individual with dilated cardiomyopathy (DCM) as well as an individual with unspecified laminopathy; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Narula N et al. J Am Coll Cardiol, 2012 Nov;60:1916-20). This variant has also been seen in a cohort of LMNA mutation carriers; however, clinical details were not provided (van Rijsingen IA et al. Eur J Heart Fail, 2013 Apr;15:376-84). Functional studies suggest that this variant affects filament biogenesis (Florwick A et al. Front Genet, 2017 Jul;8:79). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;D;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;L;L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;D;T;D;T;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
D;.;D;D;.;.;P;.;.
Vest4
MVP
MPC
0.85
ClinPred
T
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