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

gnomAD frequency: 0.00001  dbSNP: rs397517906

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-07-20	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy and arrhythmia in published literature (van Lint et al., 2019; Murdock et al., 2021); Identified in a family with arrhythmogenic cardiomyopathy with right venctricular heart failure (RVHF) and arrhythmias in published literature (Chen et al., 2022); the p.(A242V) variant was also identified in the proband's nephew who had an abnormal ECG but was absent in a sister with arrhythmogenic cardiomyopathy without RVHF. This family harbored several additional cardiogenetic variants.; 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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 30765282, 30402260, 30847666, 28679633, 34363016, 35526016, 10939567)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000770763	SCV000699970	likely pathogenic	Primary familial dilated cardiomyopathy	2020-12-28	criteria provided, single submitter	clinical testing	Variant summary: 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. Four 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 8e-06 in 251432 control chromosomes. c.725C>T has been reported in the literature in one individual affected with Arrhythmogenic right ventricular cardiomyopathy (ARVC, Vischer_2019) and individuals affected with Dilated Cardiomyopathy (van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely pathogenic (4x). 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	2023-05-31	criteria provided, single submitter	clinical testing	The p.A242V variant (also known as c.725C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. Testing at another laboratory has shown this alteration in multiple affected individuals with cardiomyopathy and/or arrhythmia and also demonstrated segregation with disease across two families (personal communication). In addition, this variant was reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) heart failure cohort; however, the affected individual also had a PKP2 variant detected (Vischer AS et al. Int. J. Cardiol., 2019 07;286:99-103). This variant has also been detected in individuals from a genetic testing cohort who were reported to have arrhythmia, unknown cardiomyopathy, dilated cardiomyopathy, or non-ischemic cardiomyopathy; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Murdock DR et al. Genet Med, 2021 12;23(12):2404-2414). This variant was detected in an additional family reported to have ARVC, arrhythmia and heart failure in which variants in other cardiac-related genes were also detected (Chen J et al. Orphanet J Rare Dis. 2022 May;17(1):183). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000801882	SCV000941681	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-05-08	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 48076). This missense change has been observed in individuals with arrhythmogenic cardiomyopathy (PMID: 30765282, 30847666, 35526016). This variant is present in population databases (rs397517906, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the LMNA protein (p.Ala242Val).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000182361	SCV000987643	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174247	SCV001337377	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258043	SCV001434872	likely pathogenic	Dilated cardiomyopathy 1A	2019-12-17	criteria provided, single submitter	clinical testing	This c.725C>T (p.Ala242Val) variant in the LMNA gene has been reported in multiple unrelated individuals, including one case with ARVC (PMID: 30765282), 4 cases of arrhythmia (PMID: 30847666). The clinical diagnostic lab LMM reported 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 (ClinVar Accession# SCV000065054.5). The c.725C>T variant is rare in the general population and has been reported twice in gnomAD. Furthermore, computational tools suggest the Alanine 242 is conserved and the change of p.Ala242Val is predicted to be deleterious. Therefore, the c.725C>T (p. Ala242Val) variant in the LMNA gene is classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798224	SCV002041924	uncertain significance	Cardiomyopathy	2020-05-06	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