ClinVar Miner

Submissions for variant NM_032667.6(BSCL2):c.269C>T (p.Ser90Leu) (rs137852973)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235980 SCV000292810 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The S90L pathogenic variant in the BSCL2 gene has been reported previously in association with BSCL2-related neuropathies, most often Silver syndrome (Windpassinger et al., 2004; Klein et al., 2014; Cen et al., 2015). This substitution alters a conserved position predicted to be within the Lumenal topological domain of the seipin protein. Functional studies indicate that S90L inhibits protein glycosylation (Windpassinger et al., 2004) which results in a misfolding of seipin in the endoplasmic reticulum leading to cell death through ER stress (Ito and Suzuki, 2007). Therefore, the presence of S90L is consistent with a diagnosis of a BSCL2-related disorder.
Invitae RCV000547334 SCV000657774 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 90 of the BSCL2 protein (p.Ser90Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with BSCL2-related neuropathy, including Silver syndrome, distal hereditary motor neuropathy V, and Charcot-Marie-Tooth disease 2, in several families (PMID: 26815532, 17486577, 25487175, 14981520, 24604904). This variant has also been reported to arise de novo in an affected family (PMID: 17486577). ClinVar contains an entry for this variant (Variation ID: 4544). Experimental studies have shown that this missense change interferes with glycosylation and leads to protein misfolding, aggregate formation, and increased degradation through the ubiquitin-proteasomal system (PMID: 14981520, 17387721, 21957196, 26815532). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004803 SCV000024979 pathogenic Spastic paraplegia 17 2004-03-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004803 SCV000608282 likely pathogenic Spastic paraplegia 17 2017-10-23 no assertion criteria provided clinical testing Variant c.461C>T (p.S154L) has not been reported in 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 and damaging by SIFT and MutationTaster2.
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000755016 SCV000882759 pathogenic Distal hereditary motor neuronopathy type 5; Spastic paraplegia 17 2019-02-11 no assertion criteria provided research

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