1-156136074-C-CATGG
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_170707.4(LMNA):c.1112_1115dup(p.Glu372AspfsTer55) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LMNA
NM_170707.4 frameshift
NM_170707.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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 1-156136074-C-CATGG is Pathogenic according to our data. Variant chr1-156136074-C-CATGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_005572.4 | c.1112_1115dup | p.Glu372AspfsTer55 | frameshift_variant | 6/10 | ENST00000677389.1 | |
LMNA | NM_170707.4 | c.1112_1115dup | p.Glu372AspfsTer55 | frameshift_variant | 6/12 | ENST00000368300.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1112_1115dup | p.Glu372AspfsTer55 | frameshift_variant | 6/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1112_1115dup | p.Glu372AspfsTer55 | frameshift_variant | 6/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461794Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727202
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2016 | Although the c.1112_1115dupTGGA pathogenic variant in the LMNA gene has not been reported toour knowledge, this variant causes a shift in reading frame starting at codon Glutamic acid 372,changing it to an Aspartic acid, and creating a premature stop codon at position 55 of the new readingframe, denoted: p.Glu372AspfsX55. This pathogenic variant is expected to result in either anabnormal, truncated protein product or loss of protein from this allele through nonsense-mediatedmRNA decay. Other frameshift variants in the LMNA gene have been reported in HGMD inassociation with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1112_1115dupTGGAvariant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. In summary, c.1112_1115dupTGGA in the LMNA gene is interpreted as a pathogenic variant. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48030). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu372Aspfs*55) 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). - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2014 | The Glu372fs variant in LMNA has been identified by our laboratory in one Caucas ian adult with DCM and ventricular tachycardia as well in his relative with AFib and AV block. Data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the pro tein?s amino acid sequence beginning at position 372 and lead to a premature ter mination codon 55 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Heterozygous loss of function of the LMNA gene is an established disease mechanism in individuals with DCM. In addition, a nother frameshift variant starting at the same codon, but leading to a premature stop codon 108 amino acids downstream, has been reported in one individual with DCM and was absent in 300 control chromosomes (Parks 2008). In summary, this va riant is likely to be pathogenic, though additional studies are required to full y establish its clinical significance. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at