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

Total submissions: 7

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