rs57830985
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5
The NM_170707.4(LMNA):c.1745G>A(p.Arg582His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
9
9
2
Clinical Significance
Conservation
PhyloP100: 9.23
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 Uncertain_significance. Variant got 4 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 1-156138534-G-A is Pathogenic according to our data. Variant chr1-156138534-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14494.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=2, Pathogenic=2}. Variant chr1-156138534-G-A is described in Lovd as [Pathogenic]. Variant chr1-156138534-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1745G>A | p.Arg582His | missense_variant | 11/12 | ENST00000368300.9 | NP_733821.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1745G>A | p.Arg582His | missense_variant | 11/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000824 AC: 2AN: 242576Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132586
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460246Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726438
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 582 of the LMNA protein (p.Arg582His). This variant is present in population databases (rs57830985, gnomAD 0.004%). This missense change has been observed in individuals with familial partial lipodystrophy (FPLD) (PMID: 10739751, 11231979, 20130076, 28641778). ClinVar contains an entry for this variant (Variation ID: 14494). 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. This variant disrupts the p.Arg582 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 22700598, 23783098), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
LMNA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 31, 2023 | The LMNA c.1745G>A variant is predicted to result in the amino acid substitution p.Arg582His. This variant has been reported in the heterozygous and homozygous states in multiple individuals with familial partial lipodystrophy (see for example, Garg et al. 2001. PubMed ID: 11231979; Akinci et al. 2017. PubMed ID: 28641778; Soyaltin et al. 2020. PubMed ID: 32685188). Different substitutions impacting the same amino acid (p.Arg582Cys, p.Arg582Ser) have also been reported in patients with partial lipodystrophy (Mory et al. 2012. PubMed ID: 22700598; Ji et al. 2013. PubMed ID: 23783098) This variant is reported in 0.0042% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156108325-G-A). This variant is interpreted as pathogenic. - |
Familial partial lipodystrophy, Dunnigan type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2024 | The p.R582H variant (also known as c.1745G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1745. The arginine at codon 582 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with atypical familial partial lipodystrophy (FPLD) in both the heterozygous and homozygous state, with severity of the disease correlated with zygosity (Garg A et al. J Clin Endocrinol Metab, 2001 Jan;86:59-65; Boschmann M et al. J Clin Endocrinol Metab, 2010 Apr;95:1634-43; Akinci B et al. Metabolism, 2017 07;72:109-119; Patni N et al. J Clin Endocrinol Metab, 2019 04;104:1099-1108; Soyaltin UE et al. Clin Diabetes Endocrinol, 2020 Jul;6:13). This variant has also been reported to segregate with disease (Speckman RA et al. Am J Hum Genet, 2000 Apr;66:1192-8; Akinci B et al. Metabolism, 2017 07;72:109-119). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2021 | This missense variant replaces arginine with histidine at codon 582 of the lamin A 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). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with familial partial lipodystrophy, but the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 15, 2023 | This missense variant replaces arginine with histidine at codon 582 of the lamin A 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). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: :c.*770G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. However, this variant has been reported in over 10 individuals affected with familial partial lipodystrophy, which is a rare condition characterized by an abnormal distribution of fatty tissue in the body and associated with metabolic involvement, such as diabetes, hyperlipidemia, and hepatosteatosis (PMID: 10739751, 11231979, 20130076, 28641778, 30418556, 30595509, 32193531, 32685188). This variant has been identified in 3/273962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the available evidence indicates that this variant is associated with familial partial lipodystrophy. However, the role of this variant in cardiomyopathy is not clear due to the lack of clinical evidence. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy. - |
not provided Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M;M;.;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
T;D;D;D;D;D
Polyphen
D;D;.;.;.;.
Vest4
MVP
MPC
1.2
ClinPred
D
GERP RS
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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