rs267607577
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_170707.4(LMNA):c.1300_1307delGCACGCAC(p.Ala434fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A434A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
LMNA
NM_170707.4 frameshift
NM_170707.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-156136351-AGCACGCAC-A is Pathogenic according to our data. Variant chr1-156136351-AGCACGCAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1300_1307delGCACGCAC | p.Ala434fs | frameshift_variant | 7/12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.1300_1307delGCACGCAC | p.Ala434fs | frameshift_variant | 7/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1300_1307delGCACGCAC | p.Ala434fs | frameshift_variant | 7/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.1300_1307delGCACGCAC | p.Ala434fs | frameshift_variant | 7/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
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 | Nov 03, 2020 | This variant has been observed in individual(s) with LMNA-related conditions (PMID: 27884249). ClinVar contains an entry for this variant (Variation ID: 179384). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala434*) in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). For these reasons, this variant has been classified as Pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 08, 2013 | The Ala434X variant in LMNA has not been reported in individuals with cardiomyop athy and data from large population studies are insufficient to assess the frequ ency of this variant in the general population. This variant introduces a deleti on of 8 bases and creates a premature termination codon at amino acid 434. This alteration is predicted to lead to a truncated or absent protein. Heterozygous l oss of function of the LMNA gene is an established disease mechanism for DCM. In summary, this variant is likely to be pathogenic, but additional studies are ne eded to fully establish its clinical significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at