ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.344A>T (p.Glu115Val) (rs794728588)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182354 SCV000234667 likely pathogenic not provided 2013-01-11 criteria provided, single submitter clinical testing p.Glu115Val (GAG>GTG): c.344 A>T in exon 1 of the LMNA gene (NM_170707.2). The Glu115Val variant in the LMNA gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu115Val results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a non-polar Valine at a position that is conserved across species. In silico analysis predicts Glu115Val is damaging to the protein structure/function. Mutations in nearby residues (Leu102Pro, Gly125Ala) have been reported in association with laminopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu115Val was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu115Val is a good candidate for a disease-causing mutation, with the information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Invitae RCV000707542 SCV000836643 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-04-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 115 of the LMNA protein (p.Glu115Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 200932). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852405 SCV000995088 likely pathogenic Familial dilated cardiomyopathy; Peripheral neuropathy 2019-06-03 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223737 SCV000280181 uncertain significance not specified 2013-01-26 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Glu115Val Based on the data reviewed below we consider it a variant of uncertain significance. We did find one online listing of the variant ( Unfortunately no clinical information is provided either about the specific individual with that variant or the cohort studied. This is a non conservative amino acid change with a negatively charged Glutamic Acid replaced with a nonpolar, neutral Valine at a residue that is highly conserved across species (with the exception of elegans and drosophila). In silico analysis with PolyPhen-2 predicts the amino acid change to be possibly damaging. Mutation taster predicts it to be disease causing. Variants in nearby codons have been reported in association with laminoapthy (p.Leu102Pro, p.Arg110Ser, p.Glu111Lys, p.Lys117Arg, p.Gly125Ala) (Stenson P et al 2009, Dittmer et al 2011, There also appears to be minimal variation in this region in the general population. The nearest missense variants in the NHLBI Exome Sequencing Project are at codons 147, 166, 175, and 189, which each only occurring in 1 out of ~6500 individuals (as of January 27th, 2013). In total, the variant has not been observed in ~6500 individuals from publicly available datasets roughly representing the general population. The variant is not listed in dbSNP or 1000 Genomes (as of January 27th, 2013). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January 25th 2013).

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