ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.976T>A (p.Ser326Thr) (rs56851164)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621488 SCV000736913 uncertain significance Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000208012 SCV000264011 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057494 SCV000337761 uncertain significance not provided 2015-12-08 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057494 SCV000088608 not provided not provided no assertion provided not provided
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755678 SCV000883086 uncertain significance Dilated cardiomyopathy 1A 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000057494 SCV000234689 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing p.Ser326Thr (TCA>ACA): c.976 T>A in exon 6 of the LMNA gene (NM_170707.2). The S326T variant in LMNA gene has been reported previously in association with Emery Dreifuss muscular dystrophy (EDMD) and was absent from 100 healthy controls (Muntoni F et al., 2006). This individuals family history was positive for molecularly confirmed X-linked EDMD, however as the proband was severely affected additional studies identified a de novo S326T sequence change in LMNA gene. The authors hypothezised that separate mutations in related proteins that interact or are involved in the same pathway, may contribute to disease severity in EDMD (Muntoni F et al., 2006). On the other hand, a simulation model used for structural and thermodynamic characterization of LMNA mutations showed that S326T did not affect noticeably the coil 2B dimerization of lamin A/C (Gangemi F et al., 2012). The S326T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (E317K, A318T, R331Q, R331P, S334N, R335Q, R335W, R336Q) have been reported in association with LMNA-related disorder, supporting the functional importance of this region of the protein. However, the S326T variant 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 not well conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s).
Invitae RCV000544253 SCV000657831 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 326 of the LMNA protein (p.Ser326Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs56851164, ExAC 0.01%). This variant has been reported in individuals affected with Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy, and late-onset scapular myopathy (PMID: 16585054, 16407522, 24503780). This variant has been reported to segregate with dilated cardiomyopathy in a single family (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 48097). 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 tolerated, but these predictions have not been confirmed by published functional 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212504 SCV000065076 uncertain significance not specified 2018-03-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ser326Thr v ariant in LMNA has been reported in 7 individuals with a range of cardio-muscula r manifestations, including 5 individuals with DCM and/or conduction system dise ase (CSD), 1 with late-onset scapular myopathy and CSD, and 1 with early-onset X -linked EDMD that also carried a pathogenic EMD variant (Muntoni 2006, Meune 200 6, Ito 2017, Hasselberg 2018). This variant has also been identified in 15/12614 6 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs56851164). In vitro functional studies provide some evidence that the p.Ser326Thr variant may not impact protein function (Gangemi 2013). However, these types of assays may not accurately represent biological fu nction. In addition, serine (Ser) at position 326 is not conserved in evolution with 5 species carrying a threonine (Thr), suggesting that this change may be to lerated. In summary, while there is some suspicion for a pathogenic role, the cl inical significance of the p.Ser326Thr variant is uncertain due to conflicting e vidence. ACMG/AMP Criteria applied: PM6; PS4; BP4, BS3_Supporting.

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