VCV002136306.4 - ClinVar

NM_024685.4(BBS10):c.180dup (p.Glu61fs)

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.

(3)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024685.4(BBS10):c.180dup (p.Glu61fs)

Variation ID: 2136306 Accession: VCV002136306.4

Type and length

Duplication, 1 bp

Location

Cytogenetic: 12q21.2 12: 76348178-76348179 (GRCh38) [ NCBI UCSC ] 12: 76741958-76741959 (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	Feb 8, 2023	Jun 17, 2024	Dec 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024685.4:c.180_181insA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024685.4:c.180dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078961.3:p.Glu61fs	frameshift
NC_000012.12:g.76348179dup
NC_000012.11:g.76741959dup
NG_016357.1:g.5264dup
NG_126112.1:g.559dup
LRG_1255:g.5264dup
LRG_1255t1:c.180dup	LRG_1255p1:p.Glu61fs

... more HGVS ... less HGVS

Protein change

E61fs

Other names

p.Glu61ArgfsTer35

Canonical SPDI

NC_000012.12:76348178:T:TT

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

Unknown function

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.

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

Links

ClinGen: CA2580086690 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.
BBS10		-	-	GRCh38 GRCh37	979	993

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.
Bardet-Biedl syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2023	RCV003037106.3
Bardet-Biedl syndrome 10	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 11, 2023	RCV003060000.3

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.
Pathogenic (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 10 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002822972.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: A heterozygous single base pair duplication in exon 1 of the BBS10 gene that results in a frameshift and premature truncation of the protein 35 … (more) A heterozygous single base pair duplication in exon 1 of the BBS10 gene that results in a frameshift and premature truncation of the protein 35 amino acids downstream to codon 61 (p.Glu61ArgfsTer35) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference region is conserved across species. In summary, this variant is classified as a pathogenic variant. (less) Clinical Features: Rod-cone dystrophy (present) , Blindness (present) , Postaxial polydactyly (present) Zygosity: Compound Heterozygote Age: 20-29 years Sex: male Ethnicity/Population group: Indian Geographic origin: India Method: DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants relevant to the clinical indication.
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441275.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 21209035‚ 20472660‚ 22773737‚ 25982971‚ 27486776 Comment: This sequence change creates a premature translational stop signal (p.Glu61Argfs35) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Glu61Argfs35) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 663 amino acid(s) of the BBS10 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 21209035). ClinVar contains an entry for this variant (Variation ID: 2136306). This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 10 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217412.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

A heterozygous single base pair duplication in exon 1 of the BBS10 gene that results in a frameshift and premature truncation of the protein 35 amino acids downstream to codon 61 (p.Glu61ArgfsTer35) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference region is conserved across species. In summary, this variant is classified as a pathogenic variant.

Comment:

This sequence change creates a premature translational stop signal (p.Glu61Argfs*35) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 663 amino acid(s) of the BBS10 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 21209035). ClinVar contains an entry for this variant (Variation ID: 2136306). This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002822972.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.	Lindstrand A	American journal of human genetics	2016	PMID: 27486776
Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome.	Scheidecker S	American journal of ophthalmology	2015	PMID: 25982971
Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes.	Redin C	Journal of medical genetics	2012	PMID: 22773737
Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance.	Feuillan PP	The Journal of clinical endocrinology and metabolism	2011	PMID: 21209035
Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population.	Billingsley G	Journal of medical genetics	2010	PMID: 20472660

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_024685.4(BBS10):c.180dup (p.Glu61fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...