ClinVar Miner

Submissions for variant NM_005097.4(LGI1):c.406C>T (p.Arg136Trp) (rs119488099)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188042 SCV000241645 pathogenic not provided 2015-01-12 criteria provided, single submitter clinical testing p.Arg136Trp (CGG>TGG): c.406 C>T in exon 4 of the LGI1 gene (NM_005097.2). The R136W missense mutation in the LGI1 gene has been reported previously in an individual with autosomal dominant partial epilepsy with auditory features (ADPEAF) (Michelucci et al., 2007). It was also reported in another family with ADPEAF; however only three out of nine individuals with the mutation had seizures, suggesting reduced penetrance associated with this mutation (Di Bonaventura et al., 2011). Functional studies demonstrate that R136W damages normal protein secretion (Di Bonaventura et al., 2011; Nobile et al., 2009). The R136W mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This is a non-conservative substitution at a position that is conserved through mammals. Therefore, based on currently available information, R136W is considered a disease-causing mutation, and its presence is consistent with a diagnosis of an LGI1-related disorder. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSYV2-1 panel(s).
Invitae RCV000005771 SCV001198641 pathogenic Familial temporal lobe epilepsy 1 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 136 of the LGI1 protein (p.Arg136Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of lateral temporal lobe epilepsy (PMID: 17562837, 21504429). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5438). This variant has been reported to affect LGI1 protein function (PMID: 25485908). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005771 SCV000025953 pathogenic Familial temporal lobe epilepsy 1 2007-06-12 no assertion criteria provided literature only

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