rs397517906
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5
The NM_170707.4(LMNA):c.725C>T(p.Ala242Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,858 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. A242E) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
8
10
2
Clinical Significance
Conservation
PhyloP100: 4.93
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 9 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156134890-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2776047.Status of the report is criteria_provided_single_submitter, 1 stars.
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, 0.835
PP5
Variant 1-156134890-C-T is Pathogenic according to our data. Variant chr1-156134890-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48076.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=9}. Variant chr1-156134890-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.725C>T | p.Ala242Val | missense_variant | 4/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.725C>T | p.Ala242Val | missense_variant | 4/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.725C>T | p.Ala242Val | missense_variant | 4/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.725C>T | p.Ala242Val | missense_variant | 4/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251432Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727236
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GnomAD4 genome
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32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:11Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2023 | Identified in patients with cardiomyopathy and arrhythmia in published literature (van Lint et al., 2019; Murdock et al., 2021); Identified in a family with arrhythmogenic cardiomyopathy with right venctricular heart failure (RVHF) and arrhythmias in published literature (Chen et al., 2022); the p.(A242V) variant was also identified in the proband's nephew who had an abnormal ECG but was absent in a sister with arrhythmogenic cardiomyopathy without RVHF. This family harbored several additional cardiogenetic variants.; Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); 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: 31447099, 30765282, 30402260, 30847666, 28679633, 34363016, 35526016, 10939567) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Dilated cardiomyopathy 1A Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, 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. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other missense and variants containing premature termination codons have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease. There are multiple phenotypes associated with this gene, however dilated cardiomyopathy type 1A (MIM#115200) is inherited in a dominant manner (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 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 intermediate filament (IF) rod domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as likely pathogenic in at least ten individuals with dilated cardiomyopathy (DCM) (ClinVar, PMIDs: 30402260, 30765282, 30847666). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant has been shown to segregate in seven DCM affected members of this individual's family, including obligate carriers. Additionally, an external laboratory has previously reported segregation in six affected individuals from two unrelated families (ClinVar). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant is known to be paternally inherited (known familial variant). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Dec 17, 2019 | This c.725C>T (p.Ala242Val) variant in the LMNA gene has been reported in multiple unrelated individuals, including one case with ARVC (PMID: 30765282), 4 cases of arrhythmia (PMID: 30847666). The clinical diagnostic lab LMM reported 3 Caucasian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affected relatives from 2 families (ClinVar Accession# SCV000065054.5). The c.725C>T variant is rare in the general population and has been reported twice in gnomAD. Furthermore, computational tools suggest the Alanine 242 is conserved and the change of p.Ala242Val is predicted to be deleterious. Therefore, the c.725C>T (p. Ala242Val) variant in the LMNA gene is classified as likely pathogenic. - |
Cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 03, 2024 | - - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 27, 2014 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 48076). This missense change has been observed in individuals with arrhythmogenic cardiomyopathy (PMID: 30765282, 30847666, 35526016). This variant is present in population databases (rs397517906, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the LMNA protein (p.Ala242Val). - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 28, 2020 | Variant summary: LMNA c.725C>T (p.Ala242Val) results in a non-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 damaging effect of the variant on protein function. One study reports that cardiac patients with an LMNA mutation located upstream of the NLS (nuclear localization signal, amino acids 417-422) have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones (Captur_2018). The variant allele was found at a frequency of 8e-06 in 251432 control chromosomes. c.725C>T has been reported in the literature in one individual affected with Arrhythmogenic right ventricular cardiomyopathy (ARVC, Vischer_2019) and individuals affected with Dilated Cardiomyopathy (van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely pathogenic (4x). According to one of these laboratories, this variant was identified in 3 Caucasian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affected relatives from 2 families (including 3 obligate carriers). At our laboratory, two sibs tested testing positive for this variant have no clinical phenotype, however they were well below the age of onset at only ages 8 and 10 years old. Additional family history was reportedly positive for DCM in their father and paternal aunt. However, no genetic testing records available on them. These data indicate that the variant is very likely to be associated with disease. Based on the evidence outlined above, until additional clinical reports supported by functional studies are identified, the variant is classified as likely pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 03, 2016 | The p.Ala242Val variant in LMNA has been identified by our laboratory in 3 Cauca sian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affecte d relatives from 2 families (including 3 obligate carriers). This variant has be en identified in 1/66618 of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517906). Although alanine (Ala) at position 242 is not well conserved in evolution, computational predict ion tools suggest that it may impact the protein. However, this information is n ot predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala242 Val variant is likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The p.A242V variant (also known as c.725C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. Testing at another laboratory has shown this alteration in multiple affected individuals with cardiomyopathy and/or arrhythmia and also demonstrated segregation with disease across two families (personal communication). In addition, this variant was reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) heart failure cohort; however, the affected individual also had a PKP2 variant detected (Vischer AS et al. Int. J. Cardiol., 2019 07;286:99-103). This variant has also been detected in individuals from a genetic testing cohort who were reported to have arrhythmia, unknown cardiomyopathy, dilated cardiomyopathy, or non-ischemic cardiomyopathy; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Murdock DR et al. Genet Med, 2021 12;23(12):2404-2414). This variant was detected in an additional family reported to have ARVC, arrhythmia and heart failure in which variants in other cardiac-related genes were also detected (Chen J et al. Orphanet J Rare Dis. 2022 May;17(1):183). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Charcot-Marie-Tooth disease type 2B1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | Aug 21, 2024 | No available literature for CMT phenotype. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;H;H;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;D;D;D;D;D;D;T;D
Polyphen
P;.;P;D;.;.;D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);.;.;.;.;
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