VCV000166723.25 - ClinVar

NM_024685.4(BBS10):c.1091del (p.Asn364fs)

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.

(13)

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/Likely 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.1091del (p.Asn364fs)

Variation ID: 166723 Accession: VCV000166723.25

Type and length

Deletion, 1 bp

Location

Cytogenetic: 12q21.2 12: 76346894 (GRCh38) [ NCBI UCSC ] 12: 76740674 (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	Mar 29, 2015	Jun 17, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024685.4:c.1091del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078961.3:p.Asn364fs
NM_024685.4:c.1091delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024685.3:c.1091delA
NC_000012.12:g.76346895del
NC_000012.11:g.76740675del
NG_016357.1:g.6549del
LRG_1255:g.6549del
LRG_1255t1:c.1091del	LRG_1255p1:p.Asn364fs

... more HGVS ... less HGVS

Protein change

N364fs

Other names

Canonical SPDI

NC_000012.12:76346893:TT: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.

Links

ClinGen: CA273303 dbSNP: rs727503818 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	925	939

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 (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000152827.15
Bardet-Biedl syndrome 10	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 20, 2024	RCV000169072.17
not provided	Pathogenic (1)	criteria provided, single submitter	May 2, 2014	RCV000723707.5
Bardet-Biedl syndrome 1	Pathogenic (1)	criteria provided, single submitter	-	RCV001004383.1

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 (May 02, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202224.5 First in ClinVar: Jan 31, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BBS10 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163355.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Mar 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 10 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217410.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Aug 04, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Bardet-Biedl syndrome (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000221174.2 First in ClinVar: Apr 01, 2015 Last updated: May 30, 2015	Publications: PubMed (1) PubMed: 20177705 Comment: The Asn364ThrfsX5 variant in BBS10 has been reported in 1 individual with Bardet Biedl syndrome in whom it was found to be in compound heterozygosity … (more) The Asn364ThrfsX5 variant in BBS10 has been reported in 1 individual with Bardet Biedl syndrome in whom it was found to be in compound heterozygosity with another frameshift variant (Muller 2010). This variant was also not identified in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 364 and lead to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less) Number of individuals with the variant: 1
Pathogenic (Jun 09, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699619.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Publications: PubMed (4) PubMed: 17106446‚ 21044901‚ 20177705‚ 23591405 Comment: Variant summary: The BBS10 c.1091delA (p.Asn364Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense … (more) Variant summary: The BBS10 c.1091delA (p.Asn364Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121092 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). It was reported in several BBS patients in either homozygosity or compound heterozygosity with a disease causing variant indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1428delC, c.1677delC). Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Aug 15, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Bardet-Biedl syndrome 10 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914602.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (4) PubMed: 20177705‚ 25366773‚ 21642631‚ 17106446 Comment: The BBS10 c.1091delA (p.Asn364ThrfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. Across four studies, the p.Asn364ThrfsTer5 … (more) The BBS10 c.1091delA (p.Asn364ThrfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. Across four studies, the p.Asn364ThrfsTer5 variant has been identified in a total of four individuals with Bardet-Biedl syndrome (BBS) including in two in a homozygous state and in two in a compound heterozygous state with a second null variant (White et al. 2007; Muller et al. 2010; Chen et al. 2011; Pierrottet et al. 2014). One homozygous individual was also heterozygous for a missense variant in the BBS6 gene (Chen et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.001676 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Asn364ThrfsTer5 variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 10 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768154.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 31196119 Comment: A heterozygous deletion variant was identified, NM_024685.4(BBS10):c.1091del in exon 2 of 2 of the BBS10 gene. This deletion is predicted to cause a frameshift from … (more) A heterozygous deletion variant was identified, NM_024685.4(BBS10):c.1091del in exon 2 of 2 of the BBS10 gene. This deletion is predicted to cause a frameshift from amino acid position 364 introducing a stop codon downstream; NP_078961.3(BBS10):p.(Asn364Thrfs*5), resulting in loss of normal protein function through truncation (half of the protein). The variant is present in the gnomAD population database at a global population frequency of 0.007% (19 heterozygotes, 0 homozygotes) with an Ashkenazi-Jewish sub-population frequency of 0.2%. It has been previously reported in patients with Bardet-Biedl syndrome (ClinVar; Manara, E. et al. (2019)). Other variants predicted to cause a truncated protein have been reported as pathogenic in individuals with Bardet-Biedl syndrome (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Likely pathogenic (Apr 09, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Bardet-Biedl syndrome 10 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220239.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 21044901‚ 21642631‚ 20177705
Pathogenic (May 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807212.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 31, 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: SCV000942345.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 20177705‚ 20472660‚ 22773737‚ 25982971‚ 27486776 Comment: This sequence change creates a premature translational stop signal (p.Asn364Thrfs5) 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.Asn364Thrfs5) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 360 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs727503818, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20177705). ClinVar contains an entry for this variant (Variation ID: 166723). 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 (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: SCV000839556.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 30614526 Age: 20-29 weeks gestation
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Bardet-Biedl syndrome Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160906.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 10 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462851.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

The Asn364ThrfsX5 variant in BBS10 has been reported in 1 individual with Bardet Biedl syndrome in whom it was found to be in compound heterozygosity with another frameshift variant (Muller 2010). This variant was also not identified in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 364 and lead to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

Comment:

Variant summary: The BBS10 c.1091delA (p.Asn364Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121092 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). It was reported in several BBS patients in either homozygosity or compound heterozygosity with a disease causing variant indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1428delC, c.1677delC). Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The BBS10 c.1091delA (p.Asn364ThrfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. Across four studies, the p.Asn364ThrfsTer5 variant has been identified in a total of four individuals with Bardet-Biedl syndrome (BBS) including in two in a homozygous state and in two in a compound heterozygous state with a second null variant (White et al. 2007; Muller et al. 2010; Chen et al. 2011; Pierrottet et al. 2014). One homozygous individual was also heterozygous for a missense variant in the BBS6 gene (Chen et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.001676 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Asn364ThrfsTer5 variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

A heterozygous deletion variant was identified, NM_024685.4(BBS10):c.1091del in exon 2 of 2 of the BBS10 gene. This deletion is predicted to cause a frameshift from amino acid position 364 introducing a stop codon downstream; NP_078961.3(BBS10):p.(Asn364Thrfs*5), resulting in loss of normal protein function through truncation (half of the protein). The variant is present in the gnomAD population database at a global population frequency of 0.007% (19 heterozygotes, 0 homozygotes) with an Ashkenazi-Jewish sub-population frequency of 0.2%. It has been previously reported in patients with Bardet-Biedl syndrome (ClinVar; Manara, E. et al. (2019)). Other variants predicted to cause a truncated protein have been reported as pathogenic in individuals with Bardet-Biedl syndrome (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

This sequence change creates a premature translational stop signal (p.Asn364Thrfs*5) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 360 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs727503818, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20177705). ClinVar contains an entry for this variant (Variation ID: 166723). 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

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
Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study.	Manara E	Italian journal of pediatrics	2019	PMID: 31196119
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
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
Syndromic and non-syndromic forms of retinitis pigmentosa: a comprehensive Italian clinical and molecular study reveals new mutations.	Pierrottet CO	Genetics and molecular research : GMR	2014	PMID: 25366773
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
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
Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes.	Chen J	Investigative ophthalmology & visual science	2011	PMID: 21642631
Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.	Schaefer E	European journal of medical genetics	2011	PMID: 21044901
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
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
Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10.	White DR	European journal of human genetics : EJHG	2007	PMID: 17106446
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BBS10	-	-	-	-
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Text-mined citations for rs727503818 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_024685.4(BBS10):c.1091del (p.Asn364fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs727503818 ...