1-156134933-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001406994.1(LMNA):c.104G>A(p.Trp35*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001406994.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.768G>A | p.Val256Val | synonymous_variant | 4/12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.768G>A | p.Val256Val | synonymous_variant | 4/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change affects codon 256 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 15 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy with conduction disease (PMID: 28679633). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200941). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 28679633). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2024 | Published functional studies demonstrate premature splicing of exon 4 which deleted the terminal 45 base pairs and resulted in the loss of 15 aa in the rod domain of LMNA (PMID: 28679633); In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34076677, 28679633) - |
Dilated cardiomyopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 16, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 14, 2017 | The p.Val256Val variant in LMNA has been identified in 1 family with DCM and sud den death and segregated with disease in >35 affected relatives (Ito 2017). Sequ encing of RNA from individuals carrying the variant showed that this variant cau ses premature splicing of exon 4, resulting in a terminal deletion of 45 bps and loss of the last 15 amino acids of the exon (Ito 2017). This variant has not be en identified in large population studies. In summary, this variant meets criter ia to be classified as pathogenic for DCM in an autosomal dominant manner based upon its functional impact and segregation in affected individuals. ACMG/AMP Cri teria applied: PS3; PP1_Strong; PM2; PP3 - |
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2024 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The c.768G>A pathogenic mutation (also known as p.V256V), located in coding exon 4, results from a G to A substitution at nucleotide position 768 of the LMNA gene. This nucleotide substitution does not change the amino acid at codon 256. This alteration has been reported in a multi-generation family with dilated cardiomyopathy (DCM) and conduction system disease, where strong disease segregation was identified (Lynch HT et al. JAMA, 1973 Sep;225:1465-70; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). This mutation was also reported in affected individuals from an additional family with a history of DCM and sudden cardiac death (Duong et al., J Biol Methods, 2017 Sept;4(3):e78). In addition, an aberrant transcript that lacks the last 45bp of exon 4 was identified in patients from the original family, as well as in mini-gene assays (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at