NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 6, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002426488.10

Allele description [Variation Report for NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)]

NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)

Genes:

BSCL2:BSCL2 lipid droplet biogenesis associated, seipin [Gene - OMIM - HGNC]
HNRNPUL2-BSCL2:HNRNPUL2-BSCL2 readthrough (NMD candidate) [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q12.3

Genomic location:

Preferred name:

NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)

Other names:

NM_001122955.3(BSCL2):c.455A>G(p.Asn152Ser); NM_001130702.2(BSCL2):c.263A>G(p.Asn88Ser); NM_032667.6(BSCL2):c.263A>G(p.Asn88Ser)

HGVS:

NC_000011.10:g.62702499T>C
NG_008461.1:g.12076A>G
NM_001122955.4:c.455A>GMANE SELECT
NM_001130702.2:c.263A>G
NM_001386027.1:c.455A>G
NM_001386028.1:c.455A>G
NM_032667.6:c.263A>G
NP_001116427.1:p.Asn152Ser
NP_001116427.1:p.Asn152Ser
NP_001124174.2:p.Asn88Ser
NP_001372956.1:p.Asn152Ser
NP_001372957.1:p.Asn152Ser
NP_116056.3:p.Asn88Ser
LRG_235t1:c.455A>G
LRG_235t2:c.263A>G
LRG_235:g.12076A>G
LRG_235p1:p.Asn152Ser
LRG_235p2:p.Asn88Ser
NC_000011.9:g.62469971T>C
NM_001122955.2:c.455A>G
NM_001122955.3:c.455A>G
NM_001122955.4:c.455A>G
NM_032667.5:c.263A>G
NR_037946.1:n.2975A>G
Q96G97:p.Asn88Ser

Protein change:

N152S; ASN88SER

Links:

UniProtKB: Q96G97#VAR_022375; OMIM: 606158.0013; dbSNP: rs137852972

NCBI 1000 Genomes Browser:

rs137852972

Molecular consequence:

NM_001122955.4:c.455A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001130702.2:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386027.1:c.455A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386028.1:c.455A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_032667.6:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_037946.1:n.2975A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002743361	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 6, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 14981520, 15732094, 16427281, 16574104, 17387721, 18585921, 18612770, 19396477, 20598714, 21957196, 22045697, 24345054, 25219579, 25454168, 27738760, 29269637, 32320108, 34085946, 34942918 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002743361

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 6, 2023)

germline

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.

Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K.

Nat Genet. 2004 Mar;36(3):271-6. Epub 2004 Feb 22.

PubMed [citation]

PMID:: 14981520

Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.

Auer-Grumbach M, Schlotter-Weigel B, Lochmüller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C; Austrian Peripheral Neuropathy Study Group..

Ann Neurol. 2005 Mar;57(3):415-24.

PubMed [citation]

PMID:: 15732094

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV002743361.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The c.263A>G (p.N88S) alteration is located in exon 3 (coding exon 2) of the BSCL2 gene. This alteration results from an A to G substitution at nucleotide position 263, causing the asparagine (N) at amino acid position 88 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the BSCL2 c.263A>G (p.N88S) alteration is classified as pathogenic for autosomal dominant BSCL2-related neurologic disorder; however, its clinical significance for autosomal recessive BSCL2-related syndrome is unclear. Based on data from gnomAD, the G allele has an overall frequency of 0.002% (4/251364) total alleles studied. The highest observed frequency was 0.01% (1/10074) of Ashkenazi Jewish alleles. This variant has been reported in multiple individuals with features of autosomal dominant BSCL2-related neurologic disorder and cosegregates with disease in multiple families (Thomas, 2022; Gentile, 2021; Fernández-Eulate, 2020; Minami, 2018; Musacchio, 2017; Ollivier, 2015; Monteiro, 2015; Rakoevi-Stojanovi, 2010; Brusse, 2009; Cafforio, 2008; van de Warrenburg, 2006; Auer-Grumbach, 2005; Windpassinger, 2004). This amino acid position is highly conserved in available vertebrate species. In vitro and in vivo functional studies demonstrate that this alteration disrupts the N-glycosylation site of seipin resulting in protein misfolding and accumulation consistent with a toxic gain-of-function effect (Lundin, 2006; Ito, 2007; Windpassinger, 2004; Ito, 2008; Fei, 2011; Yagi, 2011; Ito, 2012). Additional functional studies show aberrant neuronal electrophysiology and synaptic plasticity in vitro (Wei, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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