ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1243G>A (p.Val415Ile) (rs267607606)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057260 SCV000232224 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000057260 SCV000565112 uncertain significance not provided 2017-03-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LMNA gene. The V415I variant previously been reportedin a patient with atrial fibrillation and was also identified in one control individual (Brauch et al., 2009). The Exome AggregationConsortium (ExAC) reports V415I was observed in 3/10,270 alleles from individuals of African ancestry (Lek et al.,2016). In addition, the V415I variant is a conservative amino acid substitution, which is not likely to impactsecondary protein structure as these residues share similar properties. This substitution occurs at a position that is notconserved across species, and isoleucine is the wild-type amino acid at this position in multiple species. Furthermore,in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function. Nevertheless, functional studies by Yang et al. (2013) demonstrate that V415I is located in theNesprin-2 binding site and may affect Nesprin-2 binding.
Invitae RCV000534245 SCV000657796 uncertain significance Charcot-Marie-Tooth disease, type 2 2017-06-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 415 of the LMNA protein (p.Val415Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs267607606, ExAC 0.03%). This variant has been reported to segregate with autosomal recessive Charcot-Marie-Tooth disease in a single family (PMID: 20709679). This variant has also been reported along with a second variant (p.Gly125Ser) in an individual affected with lone atrial fibrillation, however this same combination of variants was also identified in an unaffected control individual (PMID: 19427440). ClinVar contains an entry for this variant (Variation ID: 66797). Experimental studies have shown that this missense change disrupts interactions between lamin A and one out of 55 of its binding partners tested (PMID: 24623722). Additional studies indicate that this change affects interaction with nesprin-2 and increases nuclear deformation in vitro (PMID: 23977161). In summary, this variant has uncertain impact on LMNA function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764982 SCV000896161 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysostosis; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057260 SCV000088373 not provided not provided no assertion provided not provided

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