ClinVar Miner

Submissions for variant NM_024649.4(BBS1):c.1169T>G (p.Met390Arg) (rs113624356)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000012926 SCV000807645 pathogenic Bardet-Biedl syndrome 1 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and has been found multiple times in our laboratory in affected individuals: 4 homozygotes and 2 compound heterozygotes. Heterozygotes are expected to be asymptomatic carriers.
Broad Institute Rare Disease Group,Broad Institute RCV000174408 SCV000693896 pathogenic Bardet-Biedl syndrome 2017-06-25 criteria provided, single submitter research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000082202 SCV000280850 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210319 SCV000259109 pathogenic Retinal dystrophy 2015-01-30 no assertion criteria provided clinical testing
Counsyl RCV000012926 SCV000678162 pathogenic Bardet-Biedl syndrome 1 2015-10-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082202 SCV000225702 pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000012926 SCV000611250 pathogenic Bardet-Biedl syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000082202 SCV000329106 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing The M390R variant in the BBS1 gene is one of the most common pathogenic variants in the BBS1 gene and has been reported previously in the homozygous and compound heterozygous state in multiple individuals with Bardet-Biedl syndrome (BBS) as well as in several individuals with mild BBS or nonsyndromic retinitis pigmentosa (Mykytyn et al., 2002; Beales et al., 2003; Cox et al., 2012; Estrada-Cuzcano et al., 2012). This variant has also been observed in the homozygous state in multiple patients referred for genetic testing at GeneDx. The M390R variant is observed in 347/126,644 (0.27%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The M390R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007). We interpret M390R as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000012926 SCV000246778 pathogenic Bardet-Biedl syndrome 1 2015-03-19 criteria provided, single submitter clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000012926 SCV000804595 pathogenic Bardet-Biedl syndrome 1 2016-09-01 no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000012926 SCV000373275 pathogenic Bardet-Biedl syndrome 1 2017-09-15 criteria provided, single submitter clinical testing Across a selection of available literature, the BBS1 c.1169T>G (p.Met390Arg) missense 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 (Mykytyn et al. 2002; Mykytyn et al. 2003; Chen et al. 2011). Beales et al. (2003) reported that the p.Met390Arg 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. Additionally, eight families who were triallelic for the p.Met290Arg variant and one or two other variants on other BBS genes were identified, indicating that complex inheritance may exist in some families. This variant was identified on two of 850 control chromosomes and is reported at a frequency of 0.00432 in the American sub-population of the 1000 Genomes Project. A Bbs1Met390Arg/Met390Arg knockin mouse model demonstrated mice with retinal degeneration, male infertility, and obesity (Davis et al. 2007). Functional studies in zebrafish identified the p.Met390Arg variant as a hypomorph as evidenced by partial phenotypic rescue when the variant was introduced into zebrafish embryos lacking BBS1 expression (Zaghloul et al. 2010). Based on the collective evidence, the p.Met390Arg variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000174408 SCV000699512 pathogenic Bardet-Biedl syndrome 2016-08-04 criteria provided, single submitter clinical testing 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.
Invitae RCV000174408 SCV000253934 pathogenic Bardet-Biedl syndrome 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 390 of the BBS1 protein (p.Met390Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs113624356, ExAC 0.2%). This variant is clearly defined as a Bardet-Biedl syndrome (BBS) causative allele and accounts for approximately 80% of BBS1 variants (PMID: 12118255, 12524598). In most of these cases, affected individuals were either homozygous or were compound heterozygous with a second pathogenic sequence change. While this variant has been reported to segregate with BBS in many families (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22940089, 27032803), it has also been reported in individuals affected with non-syndromic retinitis pigmentosa (PMID: 22581970, 27032803, 23143442). ClinVar contains an entry for this variant (Variation ID: 12143). Experimental studies have shown that this missense change results in photoreceptor degeneration, severe obesity, male infertility, enlarged lateral ventricles in the brain, and reduced corpus striatum in mice (PMID: 18032602) and exhibits only partial function in a zebrafish assay (PMID: 20498079, 15314642). For these reasons, this sequence change has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000174408 SCV000712198 pathogenic Bardet-Biedl syndrome 2018-02-04 criteria provided, single submitter clinical testing The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bardet-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beales 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 has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 12143). Animal models in mice have shown that this variant causes Bardet-Biedl syndrome (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
Laboratory of Medical Genetics, INSERM RCV000174408 SCV000839548 pathogenic Bardet-Biedl syndrome 2018-09-15 no assertion criteria provided provider interpretation
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000082202 SCV000926502 pathogenic not provided 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000174408 SCV000926503 pathogenic Bardet-Biedl syndrome 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504693 SCV000926793 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787785 SCV000926794 pathogenic Usher syndrome 2018-04-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases,University of Cambridge RCV000504693 SCV000598855 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases,University of Cambridge RCV000210319 SCV000598856 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
OMIM RCV000012926 SCV000033167 pathogenic Bardet-Biedl syndrome 1 2013-10-01 no assertion criteria provided literature only

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