ClinVar Miner

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

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Total submissions: 7
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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 2020-10-01 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.
Athena Diagnostics Inc RCV000235980 SCV001475547 pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. One de novo case with parental identity confirmed plus 2 unconfirmed cases.
OMIM RCV000004803 SCV000024979 pathogenic Spastic paraplegia 17 2010-09-01 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
OMIM RCV001270681 SCV001451408 pathogenic Neuronopathy, distal hereditary motor, type 5C 2010-09-01 no assertion criteria provided literature only

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