Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong
The NM_170707.4(LMNA):c.895A>G(p.Ile299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. I299T) 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 1 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_170707.4
PM2
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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
?
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=0.019576252).
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jun 26, 2017
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Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Sep 07, 2018
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 18, 2021
This variant is associated with the following publications: (PMID: 28663758, 25163546, 25351510, 25367549, 25637381, 24503780, 21883346, 27841971, 26332594, 25832542) -
Uncertain significance, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Jun 07, 2022
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not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Mar 07, 2019
Variant classified as Uncertain Significance - Favor Benign. The p.Ile299Val variant in LMNA has been reported in 1 individual with Familial Partial Lipodystrophy (FPLD2) and lipomas (it is unclear if this individual had any cardiac manifestations), segregated with disease in 2 affected relatives but was also detected in 1 assymptomatic nephew of the proband, and was absent from 100 control chromosomes (Araújo-Vilar 2011). It has also been reported in 1 individual with DCM (Pugh 2014). This variant has also been identified in 0.3% of Latino chromosomes in gnomAD. Conserved across evolutionarily distant species, however computational predictions on the impact to the protein are mixed . This data suggests that the Ile299Val variant may be benign for cardiomyopathy and Familial Partial Lipodystrophy, although additional information is needed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Mar 05, 2022
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Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre
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Familial partial lipodystrophy, Dunnigan type Uncertain:1
Uncertain significance, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Jun 01, 2014
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Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 10, 2018
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Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 17, 2017
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -