Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6
The NM_170707.4(LMNA):c.1657G>A(p.Asp553Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000296 in 1,555,816 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D553H) has been classified as Uncertain significance.
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]
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
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PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, LMNA
BP4
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BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.09031206).
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-156137702-G-A is Benign according to our data. Variant chr1-156137702-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jun 09, 2022
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with an LMNA-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 10939567, 28679633, 27884249) -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Feb 12, 2016
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Jan 20, 2021
- -
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre
-
- -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Nov 29, 2016
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Mar 10, 2019
The p.Asp553Asn variant in LMNA is classified as likely benign because it has been identified in 0.06% (15/24926) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, 2 mammals (rat and mouse) have an asparagine (Asn) at this position despite relatively nearby amino acid conservation. In addition, most computational tools do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria applied: BS1_supporting, BP4. -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Oct 18, 2019
- -
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter