ClinVar Miner

Submissions for variant NM_201253.3(CRB1):c.498_506del (p.Ile167_Gly169del) (rs398124615)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082822 SCV000114870 likely benign not specified 2013-09-25 criteria provided, single submitter clinical testing
Molecular Medicine,University of Leeds RCV000505172 SCV000611552 pathogenic Macular dystrophy 2017-10-27 criteria provided, single submitter research
GeneDx RCV000598962 SCV000709902 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The c.498_506delAATTGATGG variant in the CRB1 gene has been reported previously in association with autosomal recessive early-onset retinal dystrophies when present in the homozygous state or when in trans with another disease-causing variant (Corton et al., 2013). The c.498_506delAATTGATGG variant causes an in-frame deletion of 3 amino acid residues, denoted p.Ile167_Gly169del. The c.498_506delAATTGATGG variant is observed in 11/10150 (0.1%) alleles from individuals of Ashkenazi Jewish background, including 1 homozygous individual in large population cohorts (Lek et al., 2016). We interpret c.498_506delAATTGATGG as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000615750 SCV000731981 likely pathogenic Bestrophinopathy, autosomal recessive 2017-11-29 criteria provided, single submitter clinical testing The p.Ile98_Gly100del (NM_001257965.1 c.291_299delAATTGATGG) variant in CRB1 (al so reported as NM_201253.2:p.Ile167_Gly169del) has been previously reported in 1 homozygous and 7 compound heterozygous individuals with retinal disorders inclu ding retinal dystrophy, retinitis pigmentosa, and familial foveal retinoschisis (Corton 2013, Vincent 2016, Riera 2017). It has also been identified in 0.1% (12 4/126,500) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs748136623). This variant is a deletion of 3 amino acids at position 98-100, and it is unclear if this deletion will imp act the protein. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Ile98_Gly100del variant is likely path ogenic for retinal disorders based on its biallelic occurrence individuals with these diseases. ACMG/AMP Criteria applied: PM3 (upgraded to Strong based on mult iple occurrences), PM4 (Richards 2015).
Illumina Clinical Services Laboratory,Illumina RCV000778208 SCV000914374 pathogenic CRB1-Related Disorders 2018-08-09 criteria provided, single submitter clinical testing The CRB1 c.498_506delAATTGATGG (p.Ile167_Gly169del) variant is an inframe deletion that has been reported in at least five studies in which it is identified in a total of 10 individuals, including in one in a homozygous state and in nine in a compound heterozygous state, and in three additional alleles (Corton et al. 2013; Zaneveld et al. 2015; Sergouniotis et al. 2016; Carss et al. 2017; Shah et al. 2017). Individuals with the variant present with a range of phenotypes including early-onset retinitis pigmentosa, Stargardt macular dystrophy, isolated maculopathy, macular dystrophy, and retinal dystrophy. No individuals with the variant have been reported with Leber congenital amaurosis or pigmented paravenous chorioretinal atrophy. Control data are unavailable for this variant, which is reported at a frequency of 0.00108 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Ile167_Gly169del variant is classified as pathogenic for CRB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000798096 SCV000937693 pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2020-10-27 criteria provided, single submitter clinical testing This variant, c.498_506delAATTGATGG, results in the deletion of 3 amino acid(s) of the CRB1 protein (p.Ile167_Gly169del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748136623, ExAC 0.1%), including at least one homozygous and/or hemizygous individual. This variant has been observed in several individuals affected with retinal dystrophies (PMID: 23379534, 28181551, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96659). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000986483 SCV001135495 likely pathogenic Leber congenital amaurosis 1 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075317 SCV001240935 pathogenic Retinal dystrophy 2018-02-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000598962 SCV001246859 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000598962 SCV001447636 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV001353031 SCV001548145 likely pathogenic CRB1-related maculopathy 2021-01-30 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505172 SCV000598923 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000505172 SCV000804629 pathogenic Macular dystrophy 2016-09-01 no assertion criteria provided clinical testing
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV001250581 SCV001425448 pathogenic Leber congenital amaurosis 8 no assertion criteria provided research

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