VCV000266106.12 - ClinVar

NM_198428.3(BBS9):c.223C>T (p.Arg75Ter)

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.

(7)

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_198428.3(BBS9):c.223C>T (p.Arg75Ter)

Variation ID: 266106 Accession: VCV000266106.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p14.3 7: 33152811 (GRCh38) [ NCBI UCSC ] 7: 33192423 (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	Oct 22, 2016	Jan 25, 2025	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_198428.3:c.223C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_940820.1:p.Arg75Ter	nonsense
NM_001033604.2:c.223C>T	NP_001028776.1:p.Arg75Ter	nonsense
NM_001033605.2:c.223C>T	NP_001028777.1:p.Arg75Ter	nonsense
NM_001348036.1:c.223C>T	NP_001334965.1:p.Arg75Ter	nonsense
NM_001348037.3:c.-79C>T		5 prime UTR
NM_001348038.3:c.-55C>T		5 prime UTR
NM_001348039.3:c.-55C>T		5 prime UTR
NM_001348040.3:c.223C>T	NP_001334969.1:p.Arg75Ter	nonsense
NM_001348041.4:c.223C>T	NP_001334970.1:p.Arg75Ter	nonsense
NM_001348042.3:c.88C>T	NP_001334971.1:p.Arg30Ter	nonsense
NM_001348043.3:c.223C>T	NP_001334972.1:p.Arg75Ter	nonsense
NM_001348044.3:c.-39+22770C>T		intron variant
NM_001348045.3:c.-79C>T		5 prime UTR
NM_001348046.3:c.-39+22770C>T		intron variant
NM_001362679.1:c.223C>T	NP_001349608.1:p.Arg75Ter	nonsense
NM_014451.4:c.223C>T	NP_055266.2:p.Arg75Ter	nonsense
NR_145411.1:n.502C>T		non-coding transcript variant
NR_145412.1:n.502C>T		non-coding transcript variant
NR_145413.3:n.712C>T		non-coding transcript variant
NC_000007.14:g.33152811C>T
NC_000007.13:g.33192423C>T
NG_009306.2:g.28568C>T

... more HGVS ... less HGVS

Protein change

R75*, R30*

Other names

Canonical SPDI

NC_000007.14:33152810:C:T

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA4213903 dbSNP: rs775081992 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.
BBS9		-	-	GRCh38 GRCh37	1203	1239

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 (2)	criteria provided, single submitter	Jan 4, 2024	RCV000256453.8
Retinal vascular dystrophy	Likely pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787795.1
BBS9-related disorder	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2022	RCV003409389.4
Bardet-Biedl syndrome 9	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV003463723.6

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 (Dec 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BBS9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114933.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The BBS9 c.223C>T variant is predicted to result in premature protein termination (p.Arg75). This variant has been reported in the compound heterozygous state in two … (more) The BBS9 c.223C>T variant is predicted to result in premature protein termination (p.Arg75). This variant has been reported in the compound heterozygous state in two unrelated patients with Bardet-Biedl syndrome (Shaheen et al. 2016. PubMed ID: 27894351, Table S3; Niazi et al. 2019. PubMed ID: 31488071). We have detected this variant at PreventionGenetics in the compound heterozygous and homozygous states in two patients with BBS. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-33192423-C-T). Nonsense variants in BBS9 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Jan 04, 2024)	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: SCV002134531.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 16380913‚ 20177705‚ 31488071 Comment: This sequence change creates a premature translational stop signal (p.Arg75) in the BBS9 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg75) in the BBS9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS9 are known to be pathogenic (PMID: 16380913, 20177705). This variant is present in population databases (rs775081992, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 31488071). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 266106). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 9 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004214194.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome 9 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804834.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 9 Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005666932.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (-)	no assertion criteria provided Method: research	Bardet-Biedl syndrome Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000322803.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016	Clinical Features: Polydactyly (present) , obesity (present) , hypogonadism (present) , poor vision (present) Zygosity: Homozygote
Likely pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinal vascular dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926805.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709

Comment:

The BBS9 c.223C>T variant is predicted to result in premature protein termination (p.Arg75*). This variant has been reported in the compound heterozygous state in two unrelated patients with Bardet-Biedl syndrome (Shaheen et al. 2016. PubMed ID: 27894351, Table S3; Niazi et al. 2019. PubMed ID: 31488071). We have detected this variant at PreventionGenetics in the compound heterozygous and homozygous states in two patients with BBS. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-33192423-C-T). Nonsense variants in BBS9 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg75*) in the BBS9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS9 are known to be pathogenic (PMID: 16380913, 20177705). This variant is present in population databases (rs775081992, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 31488071). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 266106). For these reasons, this variant has been classified as Pathogenic.

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
Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report.	Niazi RK	BMC medical genetics	2019	PMID: 31488071
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Characterizing the morbid genome of ciliopathies.	Shaheen R	Genome biology	2016	PMID: 27894351
Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.	Muller J	Human genetics	2010	PMID: 20177705
Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene.	Nishimura DY	American journal of human genetics	2005	PMID: 16380913

Text-mined citations for rs775081992 ...

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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_198428.3(BBS9):c.223C>T (p.Arg75Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs775081992 ...