rs397517901
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_170707.4(LMNA):āc.350A>Gā(p.Lys117Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000038 in 1,605,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. K117T) has been classified as Uncertain significance.
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 32)
Exomes š: 0.000038 ( 1 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
1
9
10
Clinical Significance
Conservation
PhyloP100: 5.13
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.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_170707.4
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.37211412).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.350A>G | p.Lys117Arg | missense_variant | 1/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.350A>G | p.Lys117Arg | missense_variant | 1/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.350A>G | p.Lys117Arg | missense_variant | 1/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.350A>G | p.Lys117Arg | missense_variant | 1/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000560 AC: 13AN: 232112Hom.: 0 AF XY: 0.0000863 AC XY: 11AN XY: 127434
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GnomAD4 exome AF: 0.0000378 AC: 55AN: 1453484Hom.: 1 Cov.: 31 AF XY: 0.0000581 AC XY: 42AN XY: 723100
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GnomAD4 genome 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:19
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 14, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2023 | - - |
Cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2023 | This missense variant replaces lysine with arginine at codon 117 of the lamin A/C proteins. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411). Additionally, this variant has been reported in three individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 25, 2020 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2024 | Variant summary: LMNA c.350A>G (p.Lys117Arg) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 1605706 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (3.8e-05 vs 0.00025), allowing no conclusion about variant significance. c.350A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples: Fontana_2013, Rijsingen_2013, Bayram_2016, Walsh_2017, Khan_2022, and McGurk_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one publication has reported experimental evidence that this variant does not increase aggregation compared to WT protein in HEK 293 cells or C2C12 myoblasts (Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34862408, 26752647, 23328570, 34935411, 37652022, 23183350, 27532257). ClinVar contains an entry for this variant (Variation ID: 48063). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 28, 2019 | The p.Lys117Arg variant in LMNA has been previously reported in 2 individuals with DCM (one of whom carried an additional pathogenic variant in LMNA), 1 individual with LVNC, 1 individual with DCM and LVNC, and in 2 individuals with unspecified cardiomyopathy and was found to segregate with disease in 2 affected family members with LVNC from 1 family (Botto 2011, Rijsingen 2013, Fontana 2013, LMM data). This variant was also identified in the homozygous state in 1 individual with DCM and arthrogryposis (Bayram 2016). It has been identified in 0.02% (6/29936) of South Asian chromosomes by gnomAD (http://gnomAD.broadinstitute.org/). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys117Arg variant is uncertain. ACMG/AMP Criteria Applied: None. - |
Emery-Dreifuss muscular dystrophy 2, autosomal dominant Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Charcot-Marie-Tooth disease type 2B1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Congenital muscular dystrophy due to LMNA mutation Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Dilated cardiomyopathy 1A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Mar 17, 2017 | The LMNA Lys117Arg variant has been previously reported in multiple probands with various conditions. Botto et al., report this variant in 1 LVNC proband and their 2 daughters with mild LVNC (2011). It has also been reported in 2 DCM probands (Fontana M, et al., 2013; Pugh TJ, et al., 2014) it is important to note that one of the DCM probands also carried another pathogenic LMNA variant (Pugh TJ, et al., 2014). A patient with arthrogryposis features; contractures of hands and feet, myopathy, hypotonia, and dilated cardiomyopathy, was found to be harbouring both LMNA Lys117Arg and RIPK4 Val561Met in the homozygous form (Bayram Y, et al., 2016). The variant has also been reported in 2 Brugada syndrome patients (Pietrelli A, 2013) and in a Hispanic child with LVNC/DCM (LMM, ClinVar SCV000065039.4). Finally, we identified this variant in a male of Lebanese ethnicity with severe hypertrophic cardiomyopathy. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00006 which is higher then expected for an inherited heart condition. Predictions from in silico tools are conflicting (SIFT "Tolerated"; PolyPhen-2 "Benign; MutationTaster "Disease causing"). In summary, based on the lack of evidence to associate a LMNA variant as a causative gene in HCM and the elevated allele frequency, we classify LMNA Lys117Arg as a variant of 'uncertain signifigance'. - |
Mandibuloacral dysplasia with type A lipodystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 117 of the LMNA protein (p.Lys117Arg). This variant is present in population databases (rs397517901, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 2338570, 23183350, 26752647, 27532257). ClinVar contains an entry for this variant (Variation ID: 48063). 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. 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. - |
Lethal tight skin contracture syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 lysine with arginine at codon 117 of the lamin A/C proteins. 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 three individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411). Additionally, this variant has been reported in three individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 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. - |
Familial partial lipodystrophy, Dunnigan type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Dec 04, 2023 | An LMNA c.350A>G (p.Lys117Arg) variant was identified. This variant has been published in the literature in relation to cardiac disease and arthrogryposis, but to our knowledge, has not been reported in association with diabetes. This variant has been reported in the ClinVar database as a variant of uncertain significance by numerous submitters. It is observed on 61/1,605,706 alleles in the general population (gnomAD v.4.0.0). including one homozygote. Computational predictors are uncertain as to the impact of this variant on LMNA function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The p.K117R variant (also known as c.350A>G), located in coding exon 1 of the LMNA gene, results from an A to G substitution at nucleotide position 350. The lysine at codon 117 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) and LMNA-related cardiomyopathy cohorts; however, clinical details were limited (Fontana M et al. JACC Cardiovasc Imaging. 2013;6:124-6; Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med. 2017;19:192-203; Peretto G et al. Ann Intern Med, 2019 10;171:458-463; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854). This variant was also detected in the homozygous state in an individual with arthrogryposis and DCM; however, the individual was homozygous for a missense variant in the RIPK4 gene (p.V561M) as well (Bayram Y et al. J. Clin. Invest. 2016;126:762-78). This amino acid position is 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
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;L;L
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
B;.;B;B;.
Vest4
MutPred
Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);
MVP
MPC
0.80
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at