rs794728608
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_170707.4(LMNA):c.859del(p.Ala287LeufsTer193) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). 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: 1.44
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 1-156135230-TG-T is Pathogenic according to our data. Variant chr1-156135230-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135230-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.859del | p.Ala287LeufsTer193 | frameshift_variant | 5/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.859del | p.Ala287LeufsTer193 | frameshift_variant | 5/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.859del | p.Ala287LeufsTer193 | frameshift_variant | 5/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.859del | p.Ala287LeufsTer193 | frameshift_variant | 5/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2013 | The c.859delG mutation has been reported previously in a female patient diagnosed with cardiomyopathy at age 36 and limb-girdle muscular dystrophy at age 37 (Benedetti S et al., 2007; referred to as c.855delG). This mutation causes a shift in reading frame starting at codon Alanine 287, changing it to a Leucine, and creating a premature stop codon at position 193 of the new reading frame, denoted p.Ala287LeufsX193. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the LMNA gene have been reported in association with DCM. In summary, c.859delG in the LMNA gene is interpreted as a disease-causing mutation. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 08, 2015 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at