ClinVar Genomic variation as it relates to human health
NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)
Variation ID: 4544 Accession: VCV000004544.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.3 11: 62702493 (GRCh38) [ NCBI UCSC ] 11: 62469965 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Feb 20, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001122955.4:c.461C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001116427.1:p.Ser154Leu missense NM_001130702.2:c.269C>T NP_001124174.2:p.Ser90Leu missense NM_001386027.1:c.461C>T NP_001372956.1:p.Ser154Leu missense NM_001386028.1:c.461C>T NP_001372957.1:p.Ser154Leu missense NM_032667.6:c.269C>T NP_116056.3:p.Ser90Leu missense NR_037946.1:n.2981C>T non-coding transcript variant NC_000011.10:g.62702493G>A NC_000011.9:g.62469965G>A NG_008461.1:g.12082C>T LRG_235:g.12082C>T LRG_235t1:c.461C>T LRG_235p1:p.Ser154Leu LRG_235t2:c.269C>T LRG_235p2:p.Ser90Leu Q96G97:p.Ser90Leu - Protein change
- S90L, S154L
- Other names
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- Canonical SPDI
- NC_000011.10:62702492:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BSCL2 | - | - |
GRCh38 GRCh37 |
5 | 567 | |
HNRNPUL2-BSCL2 | - | - | - | GRCh38 | - | 600 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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Oct 23, 2017 | RCV000004803.7 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2023 | RCV000235980.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV000547334.7 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 11, 2019 | RCV000755016.2 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2010 | RCV001270681.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813950.1 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 6, 2016 | RCV003311647.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormal central motor function
Affected status: yes
Allele origin:
de novo
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755499.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Feb 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227228.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_strong, PP3, PM1, PM2, PM6, PS4_very_strong
Number of individuals with the variant: 3
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Pathogenic
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000657774.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Aug 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001475547.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
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. … (more)
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. (less)
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Pathogenic
(Jul 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292810.12
First in ClinVar: Jul 25, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Feb 11, 2019)
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no assertion criteria provided
Method: research
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Neuronopathy, distal hereditary motor, type 5A
Hereditary spastic paraplegia 17 (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Accession: SCV000882759.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Berardinelli-Seip congenital lipodystrophy
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004011968.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
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Pathogenic
(Sep 01, 2010)
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no assertion criteria provided
Method: literature only
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SILVER SPASTIC PARAPLEGIA SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024979.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for … (more)
In affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a c.269C-T transition (c.269C-T, NM_032667) in the BSCL2 gene, resulting in a ser90-to-leu (S90L) mutation. In an Italian mother and her 2 affected daughters with variable manifestations of autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), Luigetti et al. (2010) identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. The patients had predominant motor impairment with distal muscle weakness and atrophy of the upper and lower limbs, as well as features of spasticity. One had subclinical sensory impairment, thus expanding the phenotypic spectrum associated with this mutation. (less)
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Likely pathogenic
(Oct 23, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary spastic paraplegia 17
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000608282.1
First in ClinVar: Oct 26, 2017 Last updated: Oct 26, 2017 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Foot dorsiflexor weakness (present) , Sensorimotor neuropathy (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Hindu/Gujarati
Geographic origin: India
Method: DNA was used to perform targeted gene capture using custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. The sequences obtained are aligned to the human reference genome(GRCh37/hg19) using BWA program and analyzed using Picard and GATK version 3.6 to identify variants relevant to the clinical indication.
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924532.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955296.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Sep 01, 2010)
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no assertion criteria provided
Method: literature only
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004046657.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment on evidence:
In affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for … (more)
In affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a c.269C-T transition (c.269C-T, NM_032667) in the BSCL2 gene, resulting in a ser90-to-leu (S90L) mutation. In an Italian mother and her 2 affected daughters with variable manifestations of autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), Luigetti et al. (2010) identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. The patients had predominant motor impairment with distal muscle weakness and atrophy of the upper and lower limbs, as well as features of spasticity. One had subclinical sensory impairment, thus expanding the phenotypic spectrum associated with this mutation. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary spastic paraplegia 17
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002574754.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Usefulness of comprehensive targeted multigene panel sequencing for neuromuscular disorders in Korean patients. | Park J | Molecular genetics & genomic medicine | 2019 | PMID: 31475473 |
Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease. | Chen CX | Clinical genetics | 2019 | PMID: 31372974 |
BSCL2-Related Neurologic Disorders / Seipinopathy. | Adam MP | - | 2018 | PMID: 20301484 |
Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. | Iqbal Z | PloS one | 2017 | PMID: 28362824 |
Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. | Sun B | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 27862672 |
ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia. | Musacchio T | Journal of neurology | 2017 | PMID: 27738760 |
Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis. | Li LX | Oncotarget | 2016 | PMID: 27027447 |
Charcot-Marie-Tooth type 2 and distal hereditary motor neuropathy: Clinical, neurophysiological and genetic findings from a single-centre experience. | Luigetti M | Clinical neurology and neurosurgery | 2016 | PMID: 26989944 |
Clinical and Molecular Characterization of BSCL2 Mutations in a Taiwanese Cohort with Hereditary Neuropathy. | Hsiao CT | PloS one | 2016 | PMID: 26815532 |
Application of whole exome sequencing in undiagnosed inherited polyneuropathies. | Klein CJ | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24604904 |
Molecular characterization of seipin and its mutants: implications for seipin in triacylglycerol synthesis. | Fei W | Journal of lipid research | 2011 | PMID: 21957196 |
Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. | Ito D | Annals of neurology | 2007 | PMID: 17387721 |
Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. | Windpassinger C | Nature genetics | 2004 | PMID: 14981520 |
Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. | Magré J | Nature genetics | 2001 | PMID: 11479539 |
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Text-mined citations for rs137852973 ...
HelpRecord last updated Jun 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.