ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.949G>A (p.Glu317Lys) (rs56816490)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041379 SCV000065072 likely pathogenic Primary dilated cardiomyopathy 2014-04-10 criteria provided, single submitter clinical testing The Glu317Lys variant in LMNA has been reported in at least 2 individuals with D CM and atrioventricular block and in 1 individual with DCM, and segregated with disease in at least 1 affected relative (Arbustini 2002, Pasotti 2008, Millat 20 09 ? please note, there is likely overlap between the individuals reported by th ese studies). In addition, this variant has been identified by our laboratory in 3 families with DCM and arrhythmia, segregating with disease in one affected re lative, and in 1 individual with AV block and a family history of SCD. Data from large population studies is insufficient to assess the frequency of this varian t. Computational prediction tools and conservation analysis suggest that the Glu 317Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Variants in LMNA are prevalent in individual s with DCM and conduction system disease/arrhythmia and the presence of conducti on system disease in all but 1 family with this variant increases the likelihood that it is pathogenic. In summary, the Glu317Lys variant is likely to be pathog enic, though additional studies are required to fully establish its clinical sig nificance.
GeneDx RCV000057489 SCV000234687 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The E317K pathogenic variant in the LMNA gene has been reported in association with DCM and atrioventricular block in the heterozygous state (Arbustini et al., 2002; Pasotti et al., 2008; Pugh et al., 2014, Walsh et al., 2017). The E317K variant was also reported to segregate with disease in eight members of a family presenting with atrioventricular block type I and absence of DCM (Villa et al., 2014). The E317K variant has been seen in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and it has been classified in ClinVar as pathogenic or likely pathogenic by other clinical laboratories (SCV000657829.2; SCV00000065072.5; Landrum et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The E317K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this variant is located in the rod and coil 2 region of the LMNA gene. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret E317K in the LMNA gene as a pathogenic variant.
Invitae RCV000560270 SCV000657829 pathogenic Charcot-Marie-Tooth disease, type 2 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 317 of the LMNA protein (p.Glu317Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 21846512, 27532257). It has also been found in several individuals affected with dilated cardiomyopathy who also had atrioventricular block (PMID: 11897440, Invitae). In addition, it has been shown to segregate with isolated atrioventricular block in a large family (PMID: 25469153). ClinVar contains an entry for this variant (Variation ID: 48093). 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. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769726 SCV000901147 likely pathogenic Cardiomyopathy 2016-06-27 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057489 SCV000088603 not provided not provided no assertion provided not provided

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