ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.725C>T (p.Ala242Val) (rs397517906)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041361 SCV000065054 likely pathogenic Primary dilated cardiomyopathy 2016-02-03 criteria provided, single submitter clinical testing The p.Ala242Val variant in LMNA has been identified by our laboratory in 3 Cauca sian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affecte d relatives from 2 families (including 3 obligate carriers). This variant has be en identified in 1/66618 of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517906). Although alanine (Ala) at position 242 is not well conserved in evolution, computational predict ion tools suggest that it may impact the protein. However, this information is n ot predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala242 Val variant is likely pathogenic.
GeneDx RCV000182361 SCV000234679 likely pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing The A242V variant that is likely pathogenic was identified in the LMNA gene. This variant has been previously reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017). This same clinical laboratory has classified A242V as likely pathogenic in ClinVar, and reports that A242V was found in three Caucasian adults with either ARVC, features of ARVC, or DCM, and segregated with disease in six affected relatives from two families, including three obligate carriers (ClinVar SCV000065054.4; Landrum et al., 2016). Additionally, the A242V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, while A242V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved in mammals. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000770763 SCV000699970 likely pathogenic Familial dilated cardiomyopathy 2019-03-01 criteria provided, single submitter clinical testing Variant summary: The variant, LMNA c.725C>T (p.Ala242Val) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. One study reports that cardiac patients with an LMNA mutation located upstream of the NLS (nuclear localization signal, amino acids 417-422) have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones (Captur_2018). The variant allele was found at a frequency of 8.1e-06 in 246234 control chromosomes (gnomAD) and has been reported in the literature in at-least one individual affected with Arrhythmogenic right ventricular cardiomyopathy (ARVC, Vischer_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. According to one of these laboratories, this variant was identified in 3 Caucasian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affected relatives from 2 families (including 3 obligate carriers). At our laboratory, two sibs tested testing positive for this variant have no clinical phenotype, however they were well below the age of onset at only ages 8 and 10 years old. Additional family history was reportedly positive for DCM in their father and paternal aunt. However, no genetic testing records available on them. These data indicate that the variant is very likely to be associated with disease. Based on the evidence outlined above, until additional clinical reports supported by functional studies are identified, the variant is classified as likely pathogenic.
Ambry Genetics RCV000620828 SCV000736973 likely pathogenic Cardiovascular phenotype 2017-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Invitae RCV000801882 SCV000941681 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 242 of the LMNA protein (p.Ala242Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs397517906, ExAC 0.002%). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 48076). 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. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000182361 SCV000987643 likely pathogenic not provided criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157293 SCV000207025 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-11-27 no assertion criteria provided clinical testing

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