rs59301204
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_170707.4(LMNA):βc.992G>Aβ(p.Arg331Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,834 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 Likely pathogenic (β β ).
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 32)
Exomes π: 0.000021 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
8
7
5
Clinical Significance
Conservation
PhyloP100: 6.92
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868
PP5
Variant 1-156135956-G-A is Pathogenic according to our data. Variant chr1-156135956-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135956-G-A is described in Lovd as [Pathogenic]. Variant chr1-156135956-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.992G>A | p.Arg331Gln | missense_variant | 6/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.992G>A | p.Arg331Gln | missense_variant | 6/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.992G>A | p.Arg331Gln | missense_variant | 6/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 | |
| LMNA | ENST00000677389.1 | c.992G>A | p.Arg331Gln | missense_variant | 6/10 | NM_005572.4 | ENSP00000503633 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152204Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
6
AN:
152204
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250256Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135514
GnomAD3 exomes
AF:
AC:
3
AN:
250256
Hom.:
AF XY:
AC XY:
1
AN XY:
135514
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461630Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 727136
GnomAD4 exome
AF:
AC:
31
AN:
1461630
Hom.:
Cov.:
34
AF XY:
AC XY:
13
AN XY:
727136
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000394 AC: 6AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74346
GnomAD4 genome
AF:
AC:
6
AN:
152204
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74346
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
2
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:20Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:10Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 19, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2022 | Published functional studies demonstrate a damaging effect: decreased lamina stability (Gangemi et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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: 23349452, 19875404, 24503780, 34862408, 17377071, 26383716, 22266370, 27532257, 28436080, 28759816, 27585670, 28790152, 29382405, 30420677, 31264968, 28790155, 31383942, 30847666, 31402444, 33662488, 32880476, 10939567, 23142632, 27886618) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 09, 2019 | PS4, PP1_strong, PS3_moderate, PM2, PP3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 14, 2023 | - - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2023 | This missense variant replaces arginine with glutamine at codon 331 of the lamin A/C protein. 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). Experimental functional studies have shown that this variant may cause reduced force generation due to abnormalities of the nuclear envelope of the cardiomyocytes (PMID: 28436080, 28790152). This variant has been reported in multiple individuals affected with dilated cardiomyopathy (PMID: 19875404, 23349452, 27532257, 28790152, 35434999, 35653365, 36178741). This variant has been studied in 23 Dutch carriers affected with dilated cardiomyopathy and their family members, and have been shown to segregate with disease in multiple families (PMID: 28790152). Haplotype analysis and genealogical research have indicated that this variant is a founder mutation in the Dutch population (PMID: 28790152). This variant is associated with mild phenotype and shows a better clinical outcome than other pathogenic variants in the LMNA gene (PMID: 28790152). This variant has also been reported in individuals affected with a neuromuscular phenotype with cardiac involvement (PMID: 17377071, 29382405). This variant has been identified in 3/250256 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 10, 2020 | - - |
LMNA-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | The LMNA c.992G>A variant is predicted to result in the amino acid substitution p.Arg331Gln. This variant has primarily been reported in individuals with dilated cardiomyopathy but has also been described in individuals with partial lipodystrophy or muscle weakness (see, for example, MΓΈller et al. 2009. PubMed ID: 19875404; Hoorntje et al. 2017. PubMed ID: 28790152; Table S1, Wu et al. 2018. PubMed ID: 29382405). It has been noted to segregate with disease in multiple families and has been described as a founder variant in the Dutch population (Hoorntje et al. 2017. PubMed ID: 28790152). In vitro experimental studies indicate this variant impacts protein function (Hoorntje et al. 2017. PubMed ID: 28790152; Bollen et al. 2017. PubMed ID: 28436080; van Tienen et al 2018. PubMed ID: 30420677). Other nucleotide substitutions affecting the same amino acid (p.Arg331Pro, p.Arg331Leu) have also been described in individuals with limb-girdle muscular dystrophy and dilated cardiomyopathy (Benedetti et al. 2007. PubMed ID: 17377071; Ferradini et al. 2021. PubMed ID: 34768595). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a heterozygous change in patients with LMNA-related diseases including dilated cardiomyopathy, partial lipodystrophy and, less commonly, myotonic dystrophy (PMID: 17377071, 19875404, 26383716, 28790152, 29382405, 27886618). Additionally, it was observed to segregate with disease in multiple families (PMID: 28790152). In vitro functional studies support an impact on protein function (PMID: 28790152, 30420677). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/250256) and thus is presumed to be rare. The c.992G>A (p.Arg331Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.992G>A (p.Arg331Gln) variant is classified as Pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 25, 2020 | The p.Arg331Gln variant in LMNA has been reported in 2 individuals with muscular dystrophy and over 20 individuals with dilated cardiomyopathy (DCM) and segregated with at least 10 relatives from these families (Benedetti 2007, Moller 2009, Hazebroek 2015, Hoorntje 2017, Dalin 2017, Wu 2018). Many of these individuals had an additional variant in other DCM-related genes as well as unaffected carrier relatives, which is consistent with the observation that patients with this variant tend to have a milder phenotype compared to those with other variants in LMNA (Hoorntje 2017, Hazebroeck 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 48098) and has been identified in 0.002% (2/112956) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Hoorntje 2017). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 18, 2023 | This missense variant replaces arginine with glutamine at codon 331 of the lamin A/C protein. 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). Experimental functional studies have shown that this variant may cause reduced force generation due to abnormalities of the nuclear envelope of the cardiomyocytes (PMID: 28436080, 28790152). This variant has been reported in multiple individuals affected with dilated cardiomyopathy (PMID: 19875404, 23349452, 27532257, 28790152, 35434999, 35653365, 36178741). This variant has been studied in 23 Dutch carriers affected with dilated cardiomyopathy and their family members, and have been shown to segregate with disease in multiple families (PMID: 28790152). Haplotype analysis and genealogical research have indicated that this variant is a founder mutation in the Dutch population (PMID: 28790152). This variant is associated with mild phenotype and shows a better clinical outcome than other pathogenic variants in the LMNA gene (PMID: 28790152). This variant has also been reported in individuals affected with a neuromuscular phenotype with cardiac involvement (PMID: 17377071, 29382405). This variant has been identified in 3/250256 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 331 of the LMNA protein (p.Arg331Gln). This variant is present in population databases (rs59301204, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 19875404, 23349452, 27532257, 28790152, 29382405). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48098). 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. - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 15, 2023 | Variant summary: LMNA c.992G>A (p.Arg331Gln) results in a conservative amino acid change located in the intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250256 control chromosomes (gnomAD). c.992G>A has been reported in the literature in multiple individuals affected with dilated cardiomyopathy, partial lipodystrophy, arrhythmia and/or sinus node dysfunction and in at least one individual affected with muscle weakness (e.g. Moller_2009, Hoorntje_2017, Wu_2018). This variant has been found to segregate with the disease phenotype in multiple families of Dutch ancestry and has been described as a founder variant that is often associated with a more benign phenotype (e.g. Hoorntje_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence has found that the variant is associated with an increase in abnormalities in the nuclear membrane (nuclear blebbing, honeycomb structures, donut-shapped nuclei) compared to controls, a common feature of pathogenic LMNA variants, and is also associated with a lower myofibril desnity and reduced force development of sarcomeres (e.g. Hoorntje_2017, van Tienen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28790152, 19875404, 29382405, 30420677). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic(n=8)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Dilated cardiomyopathy 1A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Apr 04, 2020 | This variant has been previously reported as a heterozygous change in patients with LMNA-related diseases including dilated cardiomyopathy, partial lipodystrophy and, less commonly, myotonic dystrophy (PMID: 17377071, 19875404, 26383716, 28790152, 29382405, 27886618). Additionally, it was observed to segregate with disease in multiple families (PMID: 28790152). In vitro functional studies support an impact on protein function (PMID: 28790152, 30420677). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/250256) and thus is presumed to be rare. The c.992G>A (p.Arg331Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.992G>A (p.Arg331Gln) variant is classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2019 | The p.R331Q pathogenic mutation (also known as c.992G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 992. The arginine at codon 331 is replaced by glutamine, an amino acid with highly similar properties, and is located in the coiled coil region. This mutation has been detected in multiple individuals with LMNA-related findings, including dilated cardiomyopathy, arrhythmia, muscle weakness, and partial lipodystrophy; this mutation has also been described as a Dutch founder mutation and observed to segregate with disease in several families (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Møller DV et al. Eur. J. Heart Fail., 2009 Nov;11:1031-5; Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]; Wu L et al. Can J Neurol Sci, 2018 05;45:262-268). Functional studies demonstrated changes in nuclear morphology, reduced maximum force development, and increased calcium sensitivity (Bollen IAE et al. J. Physiol. (Lond.), 2017 07;595:4677-4693; Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
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
Uncertain
D
MutationAssessor
Benign
M;.;M;M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;.;P;P;.;.;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);.;.;.;
MVP
MPC
1.9
ClinPred
D
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