VCV000128532.64 - ClinVar

NM_001122955.4(BSCL2):c.1280T>C (p.Leu427Pro)

Germline

Classification

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.

(19)

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.

Conflicting classifications of pathogenicity
Uncertain risk allele(1); Benign(4); Likely benign(10)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001122955.4(BSCL2):c.1280T>C (p.Leu427Pro)

Variation ID: 128532 Accession: VCV000128532.64

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q12.3 11: 62690476 (GRCh38) [ NCBI UCSC ] 11: 62457948 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Dec 6, 2016	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001122955.4:c.1280T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001116427.1:p.Leu427Pro	missense
NM_001130702.2:c.*82T>C		3 prime UTR
NM_001386027.1:c.1286T>C	NP_001372956.1:p.Leu429Pro	missense
NM_001386028.1:c.1280T>C	NP_001372957.1:p.Leu427Pro	missense
NM_032667.6:c.1088T>C	NP_116056.3:p.Leu363Pro	missense
NR_037946.1:n.3800T>C		non-coding transcript variant
NC_000011.10:g.62690476A>G
NC_000011.9:g.62457948A>G
NG_008461.1:g.24099T>C
NG_033077.1:g.4424T>C
LRG_235:g.24099T>C
LRG_235t1:c.1280T>C	LRG_235p1:p.Leu427Pro
LRG_235t2:c.1088T>C	LRG_235p2:p.Leu363Pro

... more HGVS ... less HGVS

Protein change

L427P, L363P, L429P

Other names

Canonical SPDI

NC_000011.10:62690475:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00080 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00301

Trans-Omics for Precision Medicine (TOPMed) 0.00306

The Genome Aggregation Database (gnomAD), exomes 0.00352

Exome Aggregation Consortium (ExAC) 0.00392

1000 Genomes Project 0.00080

1000 Genomes Project 30x 0.00094

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00261

Links

ClinGen: CA200862 dbSNP: rs145649423 VarSome

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
Gene	OMIM	HI score Help 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.
BSCL2		-	-	GRCh38 GRCh37	8	576
HNRNPUL2-BSCL2	-	-	-	GRCh38	-	606

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.
not provided	Benign/Likely benign (9)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000116504.47
not specified	Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 23, 2017	RCV000174173.21
Congenital generalized lipodystrophy type 2	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 13, 2018	RCV000300263.14
Neuronopathy, distal hereditary motor, type 5A	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000357438.13
Monogenic diabetes	Benign (1)	criteria provided, single submitter	Aug 10, 2018	RCV000664139.11
Charcot-Marie-Tooth disease type 2	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001082147.16
Hereditary spastic paraplegia	Likely benign (1)	criteria provided, single submitter	Aug 16, 2021	RCV001847675.11
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	May 18, 2020	RCV002426660.9
Congenital generalized lipodystrophy type 2 Hereditary spastic paraplegia 17 Neuronopathy, distal hereditary motor, type 5C Severe neurodegenerative syndrome with lipodystrophy	Likely benign (1)	criteria provided, single submitter	Oct 14, 2021	RCV002498501.8

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.
Likely benign (May 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000150452.2 First in ClinVar: May 17, 2014 Last updated: Nov 10, 2017
Likely benign (Feb 27, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225428.5 First in ClinVar: Jun 28, 2015 Last updated: Apr 09, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BSCL2 Number of individuals with the variant: 1 Sex: mixed
Benign (Jan 28, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001145759.1 First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020	Publications: PubMed (2) PubMed: 23963299‚ 25588603
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Congenital generalized lipodystrophy type 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372861.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuronopathy, distal hereditary motor, type 5A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372862.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Mar 25, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885126.2 First in ClinVar: Nov 10, 2017 Last updated: Jan 08, 2022
Likely benign (Aug 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002106246.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Benign (Apr 09, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278907.7 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 29482223, 33111339)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259514.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
Likely benign (May 18, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002726888.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Aug 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Monogenic diabetes Affected status: unknown Allele origin: unknown	Personalized Diabetes Medicine Program, University of Maryland School of Medicine Accession: SCV000787591.2 First in ClinVar: Jul 21, 2018 Last updated: Jun 13, 2020	Comment: ACMG criteria: BS1 (0.7% in gnomAD AJ population, 0.3% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (3 homozygotes in … (more) ACMG criteria: BS1 (0.7% in gnomAD AJ population, 0.3% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (3 homozygotes in gnomAD ENF pop) [REVEL 0.257, PP3 (4 predictors), BP4 (6 predictors)= conflicting evidence, not using]= benign (less) Number of individuals with the variant: 2
Likely benign (Oct 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital generalized lipodystrophy type 2 Hereditary spastic paraplegia 17 Severe neurodegenerative syndrome with lipodystrophy Neuronopathy, distal hereditary motor, type 5C Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002804276.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain risk allele (-)	criteria provided, single submitter (K And H Uppaluri Personalized Medicine Clinic Variant Classification And Assertion Criteria Updated V 2) Method: research	Congenital generalized lipodystrophy type 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV004698134.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Publications: PubMed (3) PubMed: 35351089‚ 18690553‚ 31824185 Comment: Potent mutations in BSCL2 gene are associated with Congenital generalized lipodystrophy, type 2, which can present with insulin resistance, fatty liver and diabetes.However, the role … (more) Potent mutations in BSCL2 gene are associated with Congenital generalized lipodystrophy, type 2, which can present with insulin resistance, fatty liver and diabetes.However, the role of this particular variant rs145649423 of Congenital Generalized Lipodystrophy type 2 remains uncertain (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005219376.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493255.33 First in ClinVar: May 17, 2014 Last updated: Oct 20, 2024	Comment: BSCL2: BS2 Number of individuals with the variant: 23
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740387.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928844.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925536.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971798.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

ACMG criteria: BS1 (0.7% in gnomAD AJ population, 0.3% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (3 homozygotes in gnomAD ENF pop) [REVEL 0.257, PP3 (4 predictors), BP4 (6 predictors)= conflicting evidence, not using]= benign

Comment:

Potent mutations in BSCL2 gene are associated with Congenital generalized lipodystrophy, type 2, which can present with insulin resistance, fatty liver and diabetes.However, the role of this particular variant rs145649423 of Congenital Generalized Lipodystrophy type 2 remains uncertain

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2: a case report.	Yang Y	BMC endocrine disorders	2022	PMID: 35351089
A New Compound Heterozygous Mutation Of BSCL2 In A Chinese Zhuang Ethnic Family With Congenital Generalized Lipodystrophy.	Qin YY	Diabetes, metabolic syndrome and obesity : targets and therapy	2019	PMID: 31824185
Investigation of next-generation sequencing technologies as a diagnostic tool for amyotrophic lateral sclerosis.	Morgan S	Neurobiology of aging	2015	PMID: 25588603
Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot-Marie-Tooth neuropathy and a mutation in HSPB1.	Ylikallio E	European journal of human genetics : EJHG	2014	PMID: 23963299
Congenital generalized lipodystrophy in an Indian patient with a novel mutation in BSCL2 gene.	Shirwalkar HU	Journal of inherited metabolic disease	2008	PMID: 18690553
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BSCL2	-	-	-	-

Text-mined citations for rs145649423 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001122955.4(BSCL2):c.1280T>C (p.Leu427Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145649423 ...