ClinVar Genomic variation as it relates to human health
NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)
Germline
Classification
Help
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.
(58)
Help
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
58
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)
Variation ID: 12143 Accession: VCV000012143.128
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 66526181 (GRCh38) [ NCBI UCSC ] 11: 66293652 (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 20, 2014 Jan 13, 2025 Oct 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024649.5:c.1169T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078925.3:p.Met390Arg missense NM_001348571.2:c.*21+755A>C intron variant NC_000011.10:g.66526181T>G NC_000011.9:g.66293652T>G NG_009093.1:g.20534T>G Q8NFJ9:p.Met390Arg - Protein change
- M390R
- Other names
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NP_078925.3:p.(Met390Arg)
- Canonical SPDI
- NC_000011.10:66526180:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Exome Aggregation Consortium (ExAC) 0.00148
The Genome Aggregation Database (gnomAD), exomes 0.00151
Trans-Omics for Precision Medicine (TOPMed) 0.00210
The Genome Aggregation Database (gnomAD) 0.00212
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| BBS1 | - | - |
GRCh38 GRCh37 |
460 | 1132 | |
| ZDHHC24 | - | - | - |
GRCh38 GRCh37 |
17 | 687 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (25) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000012926.74 | |
| Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2024 | RCV000082202.56 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2023 | RCV000210319.15 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000174408.40 | |
| Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
|
Jun 23, 2019 | RCV000504693.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2018 | RCV000787785.9 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 15, 2021 | RCV002251900.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 18, 2024 | RCV002513000.10 | |
|
BBS1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 13, 2024 | RCV003390672.6 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Mar 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000246778.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
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Pathogenic
(May 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280850.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(May 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225702.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 17
Zygosity: Homozygote, Single Heterozygote
Sex: mixed
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253934.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). This variant is present in population databases (rs113624356, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome and accounts for approximately 80% of BBS1 variants. It has also been observed in individual(s) with non-syndromic retinitis pigmentosa (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22581970, 22940089, 23143442, 27032803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611250.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
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Pathogenic
(Jun 25, 2017)
|
criteria provided, single submitter
Method: research
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Bardet-Biedl syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000693896.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Polycystic kidney disease (present) , Biliary atresia (present) , Gastrointestinal malrotation (present) , Congenital heart disease (present)
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Pathogenic
(Aug 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699512.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Met390 is conserved across vertebrates and is located in the Quinoprotein alcohol dehydrogenase-like superfamily domain. An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).This variant is the most common BBS-causing mutation, explaining nearly 80% of all BBS patients (Davis_PNAS_2007), and was found in 182/121966 control chromosomes. The variant is commonly found in homozygous state in BBS patients, but has also been reported in compound heterozygous patients. It has been suggested that variants in other BBS genes (i.e. BBS2, BBS6, etc) may act as a severity modifier.In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known disease variant and has been classified as pathogenic. (less)
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Pathogenic
(Jun 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712198.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it … (more)
The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beal es 2003, Badano 2003, Fan 2004, Cox 2012). This variant has also been identified in 0.27% (347/126644) of chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs113624356). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant h as been reported by other clinical laboratories in ClinVar (Variation ID: 12143) . Animal models in mice have shown that this variant causes Bardet-Biedl syndrom e (Davis 2007). In summary, this variant meets our criteria to be classified as pathogenic for Bardet-Biedl syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3; PM3_VeryStrong; PP3 (less)
Number of individuals with the variant: 3
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Pathogenic
(Jun 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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BARDET-BIEDL SYNDROME 1
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996152.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Comment:
This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in … (more)
This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.16% (436/276714); no homozygotes are present in gnomAD. The c.1169T>G (p.Met390Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
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Pathogenic
(Nov 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001143152.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least … (more)
The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001156384.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
Number of individuals with the variant: 4
Clinical Features:
Rod-cone dystrophy (present) , Polydactyly (present) , Childhood-onset truncal obesity (present) , Delayed social development (present) , Curved phalanges of the toes (present) , Intellectual … (more)
Rod-cone dystrophy (present) , Polydactyly (present) , Childhood-onset truncal obesity (present) , Delayed social development (present) , Curved phalanges of the toes (present) , Intellectual disability (present) , Asthma (present) , Vitamin B12 deficiency (present) (less)
Zygosity: Homozygote
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Pathogenic
(Aug 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239239.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
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Bardet-Biedl syndrome
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251519.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state … (more)
The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state in an individual with non-syndromic retinitis pigmentosa (PMID: 12118255; 12677556; 23143442; 22581970; 22940089; 27032803). (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 12, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193854.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and … (more)
NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and 20498079. Classification of NM_024649.4(BBS1):c.1169T>G(M390R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: research
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Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
inherited
|
Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001424979.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
|
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Pathogenic
(Dec 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448888.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 3
Clinical Features:
Sacral dimple (present) , Tethered cord (present) , Arnold-Chiari type I malformation (present) , Syringomyelia (present) , Short palpebral fissure (present) , Myopia (disease) (present) … (more)
Sacral dimple (present) , Tethered cord (present) , Arnold-Chiari type I malformation (present) , Syringomyelia (present) , Short palpebral fissure (present) , Myopia (disease) (present) , Hypermetropia (present) , Abnormality of dental structure (present) , Agenesis of maxillary incisor (present) , Hemangioma (present) , Hip dysplasia (present) , Joint hypermobility (present) , Rectal prolapse (present) , Renal malrotation (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Bicuspid aortic valve (present) , Patent ductus arteriosus (present) , Premature thelarche (present) , Generalized hypotonia (present) , Expressive language delay (present) , Bilateral cleft lip and palate (present) , Microcephaly (present) , Conductive hearing impairment (present) , Broad nasal tip (present) , Low-set ears (present) , Full cheeks (present) , Anteverted ears (present) (less)
Sex: female
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Pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573536.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PS3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760275.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058656.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23143442, 22940089, 12677556, 12118255, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.662, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001570, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Night blindness (present) , Peripheral visual field loss (present) , Retinal detachment (present)
Zygosity: Homozygote
|
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Pathogenic
(Jan 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002072576.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022
Comment:
also identified in affected sister
|
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PP3
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Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
biparental
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515296.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
Zygosity: Homozygote
|
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Pathogenic
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002522856.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM3
Clinical Features:
Renal cyst (present) , Polycystic kidney disease (present)
|
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Pathogenic
(Aug 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
inherited
|
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University
Accession: SCV002559821.2
First in ClinVar: Feb 13, 2023 Last updated: Aug 13, 2023 |
Zygosity: Compound Heterozygote
Secondary finding: no
|
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Pathogenic
(Apr 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329106.9
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published … (more)
One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23565731, 20498079, 25982971, 22940089, 17591906, 27032803, 22998390, 22581970, 12118255, 18032602, 23943788, 27788217, 26325558, 26022370, 23143442, 28502102, 29049287, 18766993, 30609409, 12677556, 30337596, 30718709, 28559085, 30484961, 28838317, 30614526, 31028937, 31370859, 29974258, 31456290, 12524598, 12837689, 15314642, 31980526, 32581362, 34327195, 33851411, 34383976, 33886537, 31589614, 33015405, 33369054, 32037395) (less)
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Pathogenic
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002097647.2 First in ClinVar: Feb 20, 2022 Last updated: May 20, 2023 |
Observation 1:
Clinical Features:
Hyperlipidemia (present)
Zygosity: Single Heterozygote
Secondary finding: no
Observation 2:
Clinical Features:
Developmental regression (present) , Leukodystrophy (present) , Lower limb spasticity (present) , Absent speech (present)
Zygosity: Single Heterozygote
Secondary finding: no
|
|
|
Pathogenic
(Feb 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV000373275.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 22, 2023 |
Comment:
The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, … (more)
The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, the c.1169T>G variant has been reported in a homozygous state in at least 29 families with Bardet-Biedl syndrome (BBS) and in a compound heterozygous state in at least 12 families with BBS (PMID: 12118255; 12524598; 21642631). A study also reported that the c.1169T>G variant was present in 75.7% of all families with BBS1 disease-causing variants in their US cohort and 82.6% of all families with BBS1 disease-causing variants in their UK cohort (PMID: 12677556). The c.1169T>G variant is reported in the Genome Aggregation Database at a frequency of 0.03070 in the Amish population (version 3.1.2). A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602). Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic for Bardet-Biedl syndrome. (less)
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|
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Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: research
|
Bardet-Biedl syndrome
Affected status: yes
Allele origin:
germline
|
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030361.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Comment:
This variant was classified as Pathogenic based on ACMG criteria: PS4, PM2, PP3, PP5.
|
Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 2
Sex: mixed
Geographic origin: Portugal
|
|
|
Pathogenic
(Dec 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017338.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503686.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between … (more)
This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between Methionine and Arginine. The variant is not present in a known functional domain, and the Methionine residue is moderately conserved due to gaps in the alignment for approximately two-thirds of vertebrates assessed (100 vertebrates, UCSC). It is present in a large population cohort at a frequency of 0.2% (rs113624356, 444/282,790 alleles in gnomAD v2.1). This missense accounts for ~80% of BBS1 disease-associated alleles and ~30% of all Bardet-Biedl syndrome (BBS). It has been identified homozygous or compound heterozygous with a second pathogenic variant in BBS1 in a large number of clinically diagnosed BBS cases (PMID: 12118255, 12524598), and segregates with disease in multiple families (PMID: 12677556, 12837689). The phenotype of variant carriers varies from non-syndromic retinitis pigmentosa, mild forms of BBS, to classical BBS (PMID: 22940089, 23143442). A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Bardet-Biedl syndrome 1
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005052034.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000807645.3
First in ClinVar: Oct 05, 2015 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005070796.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Bardet-Biedl syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769204.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (444 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been seen in many individuals with Bardet-Biedl syndrome in both homozygous and compound heterozygous states (ClinVar, DECIPHER). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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|
Pathogenic
(Sep 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248424.27
First in ClinVar: May 09, 2020 Last updated: Dec 22, 2024 |
Comment:
BBS1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting
Number of individuals with the variant: 18
|
|
|
Pathogenic
(Oct 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003539679.3
First in ClinVar: Feb 07, 2023 Last updated: Jan 13, 2025 |
Comment:
The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution … (more)
The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution at nucleotide position 1169, causing the methionine (M) at amino acid position 390 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.157% (444/282790) total alleles studied. The highest observed frequency was 0.277% (358/129114) of European (non-Finnish) alleles. The p.M390R alteration is the most common pathogenic alteration in BBS1 and has been identified in numerous homozygous and compound heterozygous individuals with Bardet-Biedl syndrome (BBS) (Mykytyn, 2002; Estrada-Cuzcano, 2012; Charkoudian, 2013) as well as in compound heterozygous individuals with retinal dystrophies (Bravo-Gil, 2016). This amino acid position is well conserved in available vertebrate species. Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010). In addition, homozygous knock-in mice with this mutation demonstrated a phenotype similar to human BBS (Davis, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413997.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1, PM3, PS3, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 01, 2013)
|
no assertion criteria provided
Method: literature only
|
BARDET-BIEDL SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033167.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 20, 2014 |
Comment on evidence:
Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the BBS1 gene in affected members of a consanguineous Puerto Rican family with Bardet-Biedl syndrome … (more)
Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the BBS1 gene in affected members of a consanguineous Puerto Rican family with Bardet-Biedl syndrome (BBS1; 209900). The substitution results from a T-to-G transversion at nucleotide 1169 (1169T-G) in exon 12 (Mykytyn, 2002). Two other Puerto Rican families carried this mutation and the glu549-to-ter mutation (209901.0002) in compound heterozygosity. Mykytyn et al. (2002) found the M390R mutation in 22 of 60 unrelated North American probands with Bardet-Biedl syndrome of mostly northern European ancestry. Sixteen of the 22 individuals were homozygous for the variant (allele frequency = 0.32). Mykytyn et al. (2003) found that the M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. Beales et al. (2003) identified homozygous M390R alleles in asymptomatic individuals in 2 separate families. They interpreted this as consistent with an oligogenic rather than a recessive model of disease transmission, as seen in triallelic inheritance. Fan et al. (2004) reported the cases of 2 sisters homozygous for the M390R mutation. One sister, who was also heterozygous for a G169A mutation in the BBS3 gene (600151.0002), was more severely affected than the sister without the additional mutation, suggesting a modifying effect of the mutation in BBS3. In a 53-year-old woman with 'juvenile retinitis pigmentosa-like' retinal features consistent with those seen in other BBS1 patients, but who had no syndromic features, Wang et al. (2013) identified homozygosity for the M390R mutation in the BBS1 gene. The authors stated that the mutation segregated with disease in the family, and noted that such patients should be followed for the potential development of syndromic phenotypes. (less)
|
|
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Pathogenic
(Jan 30, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV000259109.1
First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016 |
|
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598855.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: NA
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: NA
Observation 3:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
Observation 4:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
Observation 5:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598856.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
|
|
|
Pathogenic
(Sep 01, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
unknown,
inherited
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804595.2
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 1
|
|
|
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: SCV000839548.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Age: 5-8 months gestation
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Usher syndrome
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926794.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160905.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
|
|
|
Pathogenic
(Oct 25, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Bardet-Biedl syndrome
Affected status: yes
Allele origin:
unknown
|
Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449189.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of … (more)
This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of 0.27%. p.Met390Arg has been reported to be the most frequent cause of Bardet-Biedl syndrome (Mykytyn et al.Nature Genet 2002;31:435-438). (less)
Number of individuals with the variant: 3
Zygosity: Homozygote
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Bardet-Biedl syndrome type 1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454320.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807269.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Likely pathogenic
(-)
|
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: SCV001742151.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
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: SCV001922626.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
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: SCV001929199.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959754.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(May 10, 2023)
|
no assertion criteria provided
Method: research
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
maternal
|
Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago
Accession: SCV003926566.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Sep 13, 2024)
|
no assertion criteria provided
Method: clinical testing
|
BBS1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120938.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants … (more)
The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants identified in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255). This variant is reported in 0.28% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as a founder variant in individuals of European ancestry (Estrada-Cuzcano et al. 2012. PubMed ID: 23143442). In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079). This variant has been reported in the compound heterozygous and homozygous state in individuals with Bardet-Biedl syndrome (Internal Data, PreventionGenetics). This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Bardet-Biedl syndrome 1
Affected status: yes
Allele origin:
germline
|
GenomeConnect, ClinGen
Accession: SCV001423443.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (disease) (present) , Abnormal retinal morphology (present) , Arrhythmia (present) , Abnormality of cardiovascular system morphology (present) , Abnormal … (more)
Abnormality of vision (present) , Myopia (disease) (present) , Abnormal retinal morphology (present) , Arrhythmia (present) , Abnormality of cardiovascular system morphology (present) , Abnormal renal morphology (present) , Misalignment of teeth (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-10-03
Testing laboratory interpretation: Pathogenic
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Bardet-Biedl syndrome
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228911.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypermetropia (present) , Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present)
Indication for testing: Diagnostic
Zygosity: Homozygote
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-01-28
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Apr 01, 2018)
|
Flagged submission
flagged submission
Method: research
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000926502 appears to be redundant with SCV000926794.
(less)
Notes: SCV000926502 appears to
(...more)
Source: NCBI
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926502.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023 |
|
|
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Pathogenic
(Apr 01, 2018)
|
Flagged submission
flagged submission
Method: research
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000926503 appears to be redundant with SCV000926794.
(less)
Notes: SCV000926503 appears to
(...more)
Source: NCBI
|
Bardet-Biedl syndrome
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926503.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Apr 01, 2018)
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Flagged submission
flagged submission
Method: research
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000926793 appears to be redundant with SCV000926794.
(less)
Notes: SCV000926793 appears to
(...more)
Source: NCBI
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926793.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023 |
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Citation text
Mykytyn, K. Personal Communication. 2002. Iowa City, Iowa
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). This variant is present in population databases (rs113624356, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome and accounts for approximately 80% of BBS1 variants. It has also been observed in individual(s) with non-syndromic retinitis pigmentosa (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22581970, 22940089, 23143442, 27032803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Met390 is conserved across vertebrates and is located in the Quinoprotein alcohol dehydrogenase-like superfamily domain. An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).This variant is the most common BBS-causing mutation, explaining nearly 80% of all BBS patients (Davis_PNAS_2007), and was found in 182/121966 control chromosomes. The variant is commonly found in homozygous state in BBS patients, but has also been reported in compound heterozygous patients. It has been suggested that variants in other BBS genes (i.e. BBS2, BBS6, etc) may act as a severity modifier.In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known disease variant and has been classified as pathogenic.
Comment:
The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beal es 2003, Badano 2003, Fan 2004, Cox 2012). This variant has also been identified in 0.27% (347/126644) of chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs113624356). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant h as been reported by other clinical laboratories in ClinVar (Variation ID: 12143) . Animal models in mice have shown that this variant causes Bardet-Biedl syndrom e (Davis 2007). In summary, this variant meets our criteria to be classified as pathogenic for Bardet-Biedl syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3; PM3_VeryStrong; PP3
Comment:
This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.16% (436/276714); no homozygotes are present in gnomAD. The c.1169T>G (p.Met390Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic.
Comment:
The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.
Comment:
The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state in an individual with non-syndromic retinitis pigmentosa (PMID: 12118255; 12677556; 23143442; 22581970; 22940089; 27032803).
Comment:
NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and 20498079. Classification of NM_024649.4(BBS1):c.1169T>G(M390R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PS3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23143442, 22940089, 12677556, 12118255, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.662, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001570, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PP3
Comment:
ACMG classification criteria: PS3, PS4, PM3
Comment:
One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23565731, 20498079, 25982971, 22940089, 17591906, 27032803, 22998390, 22581970, 12118255, 18032602, 23943788, 27788217, 26325558, 26022370, 23143442, 28502102, 29049287, 18766993, 30609409, 12677556, 30337596, 30718709, 28559085, 30484961, 28838317, 30614526, 31028937, 31370859, 29974258, 31456290, 12524598, 12837689, 15314642, 31980526, 32581362, 34327195, 33851411, 34383976, 33886537, 31589614, 33015405, 33369054, 32037395)
Comment:
The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, the c.1169T>G variant has been reported in a homozygous state in at least 29 families with Bardet-Biedl syndrome (BBS) and in a compound heterozygous state in at least 12 families with BBS (PMID: 12118255; 12524598; 21642631). A study also reported that the c.1169T>G variant was present in 75.7% of all families with BBS1 disease-causing variants in their US cohort and 82.6% of all families with BBS1 disease-causing variants in their UK cohort (PMID: 12677556). The c.1169T>G variant is reported in the Genome Aggregation Database at a frequency of 0.03070 in the Amish population (version 3.1.2). A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602). Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic for Bardet-Biedl syndrome.
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between Methionine and Arginine. The variant is not present in a known functional domain, and the Methionine residue is moderately conserved due to gaps in the alignment for approximately two-thirds of vertebrates assessed (100 vertebrates, UCSC). It is present in a large population cohort at a frequency of 0.2% (rs113624356, 444/282,790 alleles in gnomAD v2.1). This missense accounts for ~80% of BBS1 disease-associated alleles and ~30% of all Bardet-Biedl syndrome (BBS). It has been identified homozygous or compound heterozygous with a second pathogenic variant in BBS1 in a large number of clinically diagnosed BBS cases (PMID: 12118255, 12524598), and segregates with disease in multiple families (PMID: 12677556, 12837689). The phenotype of variant carriers varies from non-syndromic retinitis pigmentosa, mild forms of BBS, to classical BBS (PMID: 22940089, 23143442). A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (444 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been seen in many individuals with Bardet-Biedl syndrome in both homozygous and compound heterozygous states (ClinVar, DECIPHER). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
BBS1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting
Comment:
The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution at nucleotide position 1169, causing the methionine (M) at amino acid position 390 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.157% (444/282790) total alleles studied. The highest observed frequency was 0.277% (358/129114) of European (non-Finnish) alleles. The p.M390R alteration is the most common pathogenic alteration in BBS1 and has been identified in numerous homozygous and compound heterozygous individuals with Bardet-Biedl syndrome (BBS) (Mykytyn, 2002; Estrada-Cuzcano, 2012; Charkoudian, 2013) as well as in compound heterozygous individuals with retinal dystrophies (Bravo-Gil, 2016). This amino acid position is well conserved in available vertebrate species. Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010). In addition, homozygous knock-in mice with this mutation demonstrated a phenotype similar to human BBS (Davis, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PP1, PM3, PS3, PS4
Comment:
This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of 0.27%. p.Met390Arg has been reported to be the most frequent cause of Bardet-Biedl syndrome (Mykytyn et al.Nature Genet 2002;31:435-438).
Comment:
The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants identified in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255). This variant is reported in 0.28% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as a founder variant in individuals of European ancestry (Estrada-Cuzcano et al. 2012. PubMed ID: 23143442). In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079). This variant has been reported in the compound heterozygous and homozygous state in individuals with Bardet-Biedl syndrome (Internal Data, PreventionGenetics). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Comment:
Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). This variant is present in population databases (rs113624356, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome and accounts for approximately 80% of BBS1 variants. It has also been observed in individual(s) with non-syndromic retinitis pigmentosa (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22581970, 22940089, 23143442, 27032803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Met390 is conserved across vertebrates and is located in the Quinoprotein alcohol dehydrogenase-like superfamily domain. An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).This variant is the most common BBS-causing mutation, explaining nearly 80% of all BBS patients (Davis_PNAS_2007), and was found in 182/121966 control chromosomes. The variant is commonly found in homozygous state in BBS patients, but has also been reported in compound heterozygous patients. It has been suggested that variants in other BBS genes (i.e. BBS2, BBS6, etc) may act as a severity modifier.In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known disease variant and has been classified as pathogenic.
Comment:
The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beal es 2003, Badano 2003, Fan 2004, Cox 2012). This variant has also been identified in 0.27% (347/126644) of chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs113624356). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant h as been reported by other clinical laboratories in ClinVar (Variation ID: 12143) . Animal models in mice have shown that this variant causes Bardet-Biedl syndrom e (Davis 2007). In summary, this variant meets our criteria to be classified as pathogenic for Bardet-Biedl syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3; PM3_VeryStrong; PP3
Comment:
This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.16% (436/276714); no homozygotes are present in gnomAD. The c.1169T>G (p.Met390Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic.
Comment:
The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.
Comment:
The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state in an individual with non-syndromic retinitis pigmentosa (PMID: 12118255; 12677556; 23143442; 22581970; 22940089; 27032803).
Comment:
NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and 20498079. Classification of NM_024649.4(BBS1):c.1169T>G(M390R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PS3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23143442, 22940089, 12677556, 12118255, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.662, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001570, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PP3
Comment:
ACMG classification criteria: PS3, PS4, PM3
Comment:
One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23565731, 20498079, 25982971, 22940089, 17591906, 27032803, 22998390, 22581970, 12118255, 18032602, 23943788, 27788217, 26325558, 26022370, 23143442, 28502102, 29049287, 18766993, 30609409, 12677556, 30337596, 30718709, 28559085, 30484961, 28838317, 30614526, 31028937, 31370859, 29974258, 31456290, 12524598, 12837689, 15314642, 31980526, 32581362, 34327195, 33851411, 34383976, 33886537, 31589614, 33015405, 33369054, 32037395)
Comment:
The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, the c.1169T>G variant has been reported in a homozygous state in at least 29 families with Bardet-Biedl syndrome (BBS) and in a compound heterozygous state in at least 12 families with BBS (PMID: 12118255; 12524598; 21642631). A study also reported that the c.1169T>G variant was present in 75.7% of all families with BBS1 disease-causing variants in their US cohort and 82.6% of all families with BBS1 disease-causing variants in their UK cohort (PMID: 12677556). The c.1169T>G variant is reported in the Genome Aggregation Database at a frequency of 0.03070 in the Amish population (version 3.1.2). A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602). Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic for Bardet-Biedl syndrome.
Comment:
Clinical significance based on ACMG v2.0
Comment:
This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between Methionine and Arginine. The variant is not present in a known functional domain, and the Methionine residue is moderately conserved due to gaps in the alignment for approximately two-thirds of vertebrates assessed (100 vertebrates, UCSC). It is present in a large population cohort at a frequency of 0.2% (rs113624356, 444/282,790 alleles in gnomAD v2.1). This missense accounts for ~80% of BBS1 disease-associated alleles and ~30% of all Bardet-Biedl syndrome (BBS). It has been identified homozygous or compound heterozygous with a second pathogenic variant in BBS1 in a large number of clinically diagnosed BBS cases (PMID: 12118255, 12524598), and segregates with disease in multiple families (PMID: 12677556, 12837689). The phenotype of variant carriers varies from non-syndromic retinitis pigmentosa, mild forms of BBS, to classical BBS (PMID: 22940089, 23143442). A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (444 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been seen in many individuals with Bardet-Biedl syndrome in both homozygous and compound heterozygous states (ClinVar, DECIPHER). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
BBS1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting
Comment:
The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution at nucleotide position 1169, causing the methionine (M) at amino acid position 390 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.157% (444/282790) total alleles studied. The highest observed frequency was 0.277% (358/129114) of European (non-Finnish) alleles. The p.M390R alteration is the most common pathogenic alteration in BBS1 and has been identified in numerous homozygous and compound heterozygous individuals with Bardet-Biedl syndrome (BBS) (Mykytyn, 2002; Estrada-Cuzcano, 2012; Charkoudian, 2013) as well as in compound heterozygous individuals with retinal dystrophies (Bravo-Gil, 2016). This amino acid position is well conserved in available vertebrate species. Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010). In addition, homozygous knock-in mice with this mutation demonstrated a phenotype similar to human BBS (Davis, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PP1, PM3, PS3, PS4
Comment:
This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of 0.27%. p.Met390Arg has been reported to be the most frequent cause of Bardet-Biedl syndrome (Mykytyn et al.Nature Genet 2002;31:435-438).
Comment:
The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants identified in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255). This variant is reported in 0.28% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as a founder variant in individuals of European ancestry (Estrada-Cuzcano et al. 2012. PubMed ID: 23143442). In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079). This variant has been reported in the compound heterozygous and homozygous state in individuals with Bardet-Biedl syndrome (Internal Data, PreventionGenetics). This variant is interpreted as pathogenic.
Comment:
Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Comment:
Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
| Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis. | Panneman DM | Frontiers in cell and developmental biology | 2023 | PMID: 36819107 |
| High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
| Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B. | Viehl L | Pediatric nephrology (Berlin, Germany) | 2023 | PMID: 35695966 |
| Bardet-Biedl Syndrome Overview. | Adam MP | - | 2023 | PMID: 20301537 |
| Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy. | Karali M | Scientific reports | 2022 | PMID: 36460718 |
| Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort. | Nasser F | Genes | 2022 | PMID: 35886001 |
| Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome. | Perea-Romero I | NPJ genomic medicine | 2022 | PMID: 35835773 |
| Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population. | Zhu J | Genes | 2022 | PMID: 35456422 |
| Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies. | Del Pozo-Valero M | Investigative ophthalmology & visual science | 2022 | PMID: 35119454 |
| Kidney failure in Bardet-Biedl syndrome. | Meyer JR | Clinical genetics | 2022 | PMID: 35112343 |
| Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project. | Best S | Journal of medical genetics | 2022 | PMID: 34716235 |
| BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa. | Fadaie Z | Journal of medical genetics | 2022 | PMID: 33910932 |
| Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
| Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10. | Grudzinska Pechhacker MK | Investigative ophthalmology & visual science | 2021 | PMID: 34940782 |
| Genetic testing and diagnosis of inherited retinal diseases. | Lam BL | Orphanet journal of rare diseases | 2021 | PMID: 34906171 |
| Compound Heterozygous Mutations in the BBS-1 Gene and its Clinical Presentation: A Case Report. | Michelen-Gómez E | Puerto Rico health sciences journal | 2021 | PMID: 34792930 |
| 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. | 100,000 Genomes Project Pilot Investigators | The New England journal of medicine | 2021 | PMID: 34758253 |
| Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. | Schon KR | BMJ (Clinical research ed.) | 2021 | PMID: 34732400 |
| A Genotype-Phenotype Analysis of the Bardet-Biedl Syndrome in Puerto Rico. | Guardiola GA | Clinical ophthalmology (Auckland, N.Z.) | 2021 | PMID: 34526762 |
| NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases. | Perea-Romero I | Human genetics | 2021 | PMID: 34448047 |
| Updating the Genetic Landscape of Inherited Retinal Dystrophies. | García Bohórquez B | Frontiers in cell and developmental biology | 2021 | PMID: 34327195 |
| Molecular genetics of inherited retinal degenerations in Icelandic patients. | Thorsteinsson DA | Clinical genetics | 2021 | PMID: 33851411 |
| Panel-based genetic testing for inherited retinal disease screening 176 genes. | Sheck LHN | Molecular genetics & genomic medicine | 2021 | PMID: 33749171 |
| Ciliopathies: Coloring outside of the lines. | Strong A | American journal of medical genetics. Part A | 2021 | PMID: 33369054 |
| A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome. | Delvallée C | Clinical genetics | 2021 | PMID: 33169370 |
| Clinical characteristics and ultra-widefield fundus image analysis of two siblings with Bardet-Biedl syndrome type 1 p.Met390Arg variant. | Muns SM | American journal of ophthalmology case reports | 2020 | PMID: 33015405 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. | Weisschuh N | Human mutation | 2020 | PMID: 32531858 |
| Comprehensive genomic diagnosis of inherited retinal and optical nerve disorders reveals hidden syndromes and personalized therapeutic options. | Diñeiro M | Acta ophthalmologica | 2020 | PMID: 32483926 |
| Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32037395 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. | Hanany M | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31964843 |
| A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). | Sharon D | Human mutation | 2020 | PMID: 31456290 |
| Inherited retinal disease in Norway - a characterization of current clinical and genetic knowledge. | Holtan JP | Acta ophthalmologica | 2020 | PMID: 31429209 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa. | Takahashi VKL | Orphanet journal of rare diseases | 2019 | PMID: 31370859 |
| Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania. | Crowgey EL | The Journal of molecular diagnostics : JMD | 2019 | PMID: 31028937 |
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| 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 |
| Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
| Retrotransposon insertion as a novel mutational event in Bardet-Biedl syndrome. | Tavares E | Molecular genetics & genomic medicine | 2019 | PMID: 30484961 |
| A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies. | Ezquerra-Inchausti M | Scientific reports | 2018 | PMID: 30337596 |
| Generation of induced pluripotent stem cells, KCi001-A derived from a Bardet-Biedl syndrome patient compound heterozygous for the BBS1 variants c.1169T>G/c.1135G>C. | Hey CAB | Stem cell research | 2018 | PMID: 30142598 |
| Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy. | Stokman MF | Pediatric nephrology (Berlin, Germany) | 2018 | PMID: 29974258 |
| Beneficial Outcomes of Sleeve Gastrectomy in a Morbidly Obese Patient With Bardet-Biedl Syndrome. | Boscolo M | Journal of the Endocrine Society | 2017 | PMID: 29264490 |
| Applying next generation sequencing with microdroplet PCR to determine the disease-causing mutations in retinal dystrophies. | Wang X | BMC ophthalmology | 2017 | PMID: 28838317 |
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome. | Forsythe E | Journal of the American Society of Nephrology : JASN | 2017 | PMID: 27659767 |
| Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis. | Wang X | PloS one | 2016 | PMID: 27788217 |
| Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel. | Bravo-Gil N | Scientific reports | 2016 | PMID: 27032803 |
| Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. | Ellingford JM | Ophthalmology | 2016 | PMID: 26872967 |
| Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. | Tammimies K | JAMA | 2015 | PMID: 26325558 |
| Apparent Usher Syndrome Caused by the Combination of BBS1-Associated Retinitis Pigmentosa and SLC26A4-Associated Deafness. | DeLuca AP | JAMA ophthalmology | 2015 | PMID: 26022370 |
| 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 |
| BBS mutations modify phenotypic expression of CEP290-related ciliopathies. | Zhang Y | Human molecular genetics | 2014 | PMID: 23943788 |
| Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. | Wang X | Journal of medical genetics | 2013 | PMID: 23847139 |
| Choroidal neovascularization in Bardet-Biedl syndrome. | Charkoudian LD | Ophthalmic genetics | 2013 | PMID: 23565731 |
| Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome. | Ashkinadze E | Clinical genetics | 2013 | PMID: 22998390 |
| BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome. | Estrada-Cuzcano A | Archives of ophthalmology (Chicago, Ill. : 1960) | 2012 | PMID: 23143442 |
| Phenotypic expression of Bardet-Biedl syndrome in patients homozygous for the common M390R mutation in the BBS1 gene. | Cox KF | Vision research | 2012 | PMID: 22940089 |
| A paradigm shift in the delivery of services for diagnosis of inherited retinal disease. | O'Sullivan J | Journal of medical genetics | 2012 | PMID: 22581970 |
| Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes. | Chen J | Investigative ophthalmology & visual science | 2011 | PMID: 21642631 |
| Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. | Janssen S | Human genetics | 2011 | PMID: 21052717 |
| Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome. | Zaghloul NA | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20498079 |
| A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands. | Hjortshøj TD | The British journal of ophthalmology | 2009 | PMID: 18669544 |
| Bardet-biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation. | Cannon PS | Ophthalmic genetics | 2008 | PMID: 18766993 |
| Retinal morphology in patients with BBS1 and BBS10 related Bardet-Biedl Syndrome evaluated by Fourier-domain optical coherence tomography. | Gerth C | Vision research | 2008 | PMID: 17980398 |
| A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. | Davis RE | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 18032602 |
| Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. | Fan Y | Nature genetics | 2004 | PMID: 15314642 |
| Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. | Badano JL | Human molecular genetics | 2003 | PMID: 12837689 |
| Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. | Beales PL | American journal of human genetics | 2003 | PMID: 12677556 |
| Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1). | Mykytyn K | American journal of human genetics | 2003 | PMID: 12524598 |
| Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. | Mykytyn K | Nature genetics | 2002 | PMID: 12118255 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BBS1 | - | - | - | - |
| Mykytyn, K. Personal Communication. 2002. Iowa City, Iowa | - | - | - | - |
| - | - | - | - | DOI: doi:10.1155/2023/2564200 |
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Text-mined citations for rs113624356 ...
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Record last updated Jan 13, 2025
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