VCV000001147.18 - ClinVar

NM_152618.3(BBS12):c.1063C>T (p.Arg355Ter)

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.

(12)

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_152618.3(BBS12):c.1063C>T (p.Arg355Ter)

Variation ID: 1147 Accession: VCV000001147.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q27 4: 122742955 (GRCh38) [ NCBI UCSC ] 4: 123664110 (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 20, 2014	Jun 17, 2024	Mar 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152618.3:c.1063C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689831.2:p.Arg355Ter	nonsense
NM_001178007.2:c.1063C>T	NP_001171478.1:p.Arg355Ter	nonsense
NC_000004.12:g.122742955C>T
NC_000004.11:g.123664110C>T
NG_021203.1:g.15254C>T

... more HGVS ... less HGVS

Protein change

R355*

Other names

Canonical SPDI

NC_000004.12:122742954: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) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA251706 OMIM: 610683.0001 dbSNP: rs121918327 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.
BBS12		-	-	GRCh38 GRCh37	778	805

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 12	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 16, 2024	RCV000001206.16
Bardet-Biedl syndrome	Pathogenic (2)	criteria provided, single submitter	Sep 10, 2023	RCV000538405.7
Abnormal cardiovascular system morphology Inability to walk Polydactyly, postaxial, type A1 Visual impairment	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626780.2
Bardet-Biedl syndrome 1	Pathogenic (1)	no assertion criteria provided	May 10, 2023	RCV003228891.1

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.
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 12 Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV001156389.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020	Number of individuals with the variant: 1 Clinical Features: Retinal dystrophy (present) , Polydactyly (present) , Intellectual disability (present) , Obesity (present) , Delayed speech and language development (present) , Nyctalopia (present) , Severe … (more) Retinal dystrophy (present) , Polydactyly (present) , Intellectual disability (present) , Obesity (present) , Delayed speech and language development (present) , Nyctalopia (present) , Severe Myopia (present) (less)
Pathogenic (Apr 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 12 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002814272.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 08, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Bardet-Biedl syndrome 12 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680151.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inability to walk Abnormal cardiovascular system morphology Postaxial polydactyly Visual impairment Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747483.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Mar 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 12 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370443.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Pathogenic (Sep 10, 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: SCV000636538.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17160889‚ 23591405 Comment: This sequence change creates a premature translational stop signal (p.Arg355) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg355) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 356 amino acid(s) of the BBS12 protein. This variant is present in population databases (rs121918327, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 17160889, 23591405). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1147). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 12 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211673.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 01, 2007)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 12 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021356.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2014	Publications: PubMed (1) PubMed: 17160889 Comment on evidence: In 2 consanguineous Gypsy families, not known to be related and partially settled in 2 different regions of France, with Bardet-Biedl syndrome (BBS12; 615989), Stoetzel … (more) In 2 consanguineous Gypsy families, not known to be related and partially settled in 2 different regions of France, with Bardet-Biedl syndrome (BBS12; 615989), Stoetzel et al. (2007) identified homozygosity for the same homozygous nonsense mutation in the BBS12 gene, 1062C-T, that resulted in an arg355-to-stop (R355X) substitution in the gene product. (less)
Pathogenic (Nov 27, 2017)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome 12 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132342.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Publications: PubMed (1) PubMed: 17160889
Pathogenic (May 10, 2023)	no assertion criteria provided Method: research	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: biparental, inherited, unknown	Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago Accession: SCV003926581.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Observation 1: Observation 2: Observation 3: Observation 4: Observation 5: Observation 6: Observation 7: Observation 8:
Pathogenic (Sep 15, 2018)	no assertion criteria provided Method: provider interpretation	Bardet-Biedl syndrome Affected status: yes Allele origin: germline	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University Study: French fetal BBS cohort Accession: SCV000839573.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (1) PubMed: 30614526 Ethnicity/Population group: Gypsy
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 12 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462013.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

This sequence change creates a premature translational stop signal (p.Arg355*) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 356 amino acid(s) of the BBS12 protein. This variant is present in population databases (rs121918327, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 17160889, 23591405). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1147). 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
Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.	Mary L	Clinical genetics	2019	PMID: 30614526
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies.	Glöckle N	European journal of human genetics : EJHG	2014	PMID: 23591405
Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.	Stoetzel C	American journal of human genetics	2007	PMID: 17160889

Text-mined citations for rs121918327 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_152618.3(BBS12):c.1063C>T (p.Arg355Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918327 ...