Submissions for variant NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)

gnomAD frequency: 0.00001  dbSNP: rs137852973

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235980	SCV000292810	pathogenic	not provided	2021-07-26	criteria provided, single submitter	clinical testing	Published 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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21957196, 18325928, 27549087, 28668300, 14981520, 20806400, 17387721, 26815532, 26989944, 27862672, 28362824, 27027447, 31211173, 31372974, 30835347, 32489946, 34504732, 18790819, 11479539, 25487175, 17486577, 27738760, 24604904, 33726816)
Invitae	RCV000547334	SCV000657774	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 90 of the BSCL2 protein (p.Ser90Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BSCL2-related neuropathy, including Silver syndrome, distal hereditary motor neuropathy V, and Charcot-Marie-Tooth disease 2 (PMID: 14981520, 17486577, 24604904, 25487175, 26815532). 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: 4544). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BSCL2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BSCL2 function (PMID: 14981520, 17387721, 21957196, 26815532). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813950	SCV001755499	likely pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235980	SCV004227228	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PM2, PM6, PS4_very_strong
OMIM	RCV000004803	SCV000024979	pathogenic	Hereditary 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	Hereditary 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	Neuronopathy, distal hereditary motor, type 5A; Hereditary spastic paraplegia 17	2019-02-11	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000235980	SCV001924532	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235980	SCV001955296	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000004803	SCV002574754	not provided	Hereditary spastic paraplegia 17		no assertion provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003311647	SCV004011968	uncertain significance	Berardinelli-Seip congenital lipodystrophy	2016-01-06	no assertion criteria provided	literature only
OMIM	RCV001270681	SCV004046657	pathogenic	Neuronopathy, distal hereditary motor, type 5C	2010-09-01	no assertion criteria provided	literature only