11-66526181-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_024649.5(BBS1):c.1169T>G(p.Met390Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,614,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024649.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BBS1 | ENST00000318312.12 | c.1169T>G | p.Met390Arg | missense_variant | Exon 12 of 17 | 1 | NM_024649.5 | ENSP00000317469.7 | ||
| ENSG00000256349 | ENST00000419755.3 | c.1280T>G | p.Met427Arg | missense_variant | Exon 12 of 17 | 2 | ENSP00000398526.3 |
Frequencies
GnomAD3 genomes 0.00205 AC: 312AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00151 AC: 380AN: 251388Hom.: 0 AF XY: 0.00163 AC XY: 221AN XY: 135858
GnomAD4 exome AF: 0.00274 AC: 4010AN: 1461852Hom.: 2 Cov.: 31 AF XY: 0.00268 AC XY: 1952AN XY: 727236
GnomAD4 genome 0.00205 AC: 312AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160AN XY: 74488
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 1 Pathogenic:25Other:1
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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. -
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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. -
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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. -
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This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PP3 -
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. -
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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. -
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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 -
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. -
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. -
NM_024649.5(BBS1):c.1169T>G;p.Met390Arg was identified in a patient with Bardet-Biedl syndrome in trans with a 3k bp deletion that results in exon 10-11 skipping with suggested ACMG/AMP classification as "Pathogenic". -
not provided Pathogenic:12
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) -
PP1, PM3, PS3, PS4 -
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BBS1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting -
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. -
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Bardet-Biedl syndrome Pathogenic:10Other:1
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 -
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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). -
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. -
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 95%. 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. -
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). -
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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. -
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Clinical significance based on ACMG v2.0 -
Retinal dystrophy Pathogenic:4
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Retinitis pigmentosa Pathogenic:3
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Usher syndrome Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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. -
See cases Pathogenic:1
ACMG classification criteria: PS3, PS4, PM3 -
BBS1-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at