ClinVar Miner

Submissions for variant NM_000104.3(CYP1B1):c.1103G>A (p.Arg368His) (rs79204362)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844695 SCV000221184 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg368His var iant in CYP1B1 has been reported in the homozygous or compound heterozygous stat e in several individuals of varying ethnic backgrounds with primary congenital g laucoma (Bejjani 2000, Reddy 2003, Chitsazian 2007, de Melo 2015, Rauf 2016, Yan g 2017) and functional studies suggest an impact to enzyme function (Choudhary 2 008, Pasutto 2010, Mookherjee 2012, Kabra 2017). However, this variant has also been identified in the homozygous or compound heterozygous state in at least 8 unaffected individuals (Bejjani 2000, Alsaif 2018) and has been identified in 3. 1% (939/30622) of South Asian chromosomes, 2.2% (222/10030) of Ashkenazi Jewish chromosomes, and 13 homozygotes in the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org). It was also identified at an allele frequency of 1.6% in a Saudi Arabian population cohort and 2.4% in a Qatari population cohort (Alsaif 2018, Fakhro 2016). These allele frequencies are higher than the maximu m expected allele frequency for a pathogenic variant in the CYP1B1 gene. In summ ary, the clinical significance of the p.Arg368His variant is uncertain due to co nflicting evidence. ACMG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PP3 , BA1, BS2.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000489962 SCV000228774 pathogenic not provided 2015-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000489962 SCV000577511 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing The R368H variant has been published in association with primary congenital glaucoma (Pasutto et al., 2010; Bejjani et al., 2000). The R368H variant has also been reported in healthy controls and in an unaffected homozygote who had three affected homozygous siblings (Lopez-Garrido et al., 2010; Bejjani et al., 2000). Missense variants in the same residue (R368C, R368L) have been reported in the homozygous and heterozygous states in association with primary congenital glaucoma (Chitsazian et al., 2007; Chen et al., 2008). The R368H variant is observed in 460/16278 (2.9%) alleles from individuals of South Asian background, including 10 homozygous individuals, in the ExAC dataset (Lek et al., 2016). The R368H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In vitro functional studies demonstrated that the R368H variant results in a loss-of-function in comparison to wild-type protein (Choudhary et al., 2008; Mookherjee et al., 2012). While in vitro functional studies clearly demonstrate a loss of function and this variant has been identified in many affected individuals, it is clearly not resulting in a disease phenotype in all individuals who harbor this variant. It would seem that the R368H variant either has reduced penetrance in certain individuals or there are other shared variants among affected individuals that results in the disease phenotype. Therefore this variant is considered to be of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000778148 SCV000914279 pathogenic CYP1B1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing Across a selection of the available literature, the CYP1B1 c.1103G>A (p.Arg368His) missense variant has been reported in a total of 78 individuals with a spectrum of eye disorders. Within this group, the p.Arg368His variant was identified in a homozygous state in 31 individuals, in a compound heterozygous state in 17 individuals, and in a heterozygous state in 30 individuals. Primary congenital glaucoma was the most commonly described phenotype, however other forms of childhood-onset and adulthood-onset glaucoma, as well as Peter's anomaly, Rieger's anomaly, and a case of micropthalmia with iris and fundal colobomas were also reported (Bejjani et al. 2000; Panicker et al. 2002; Vincent et al. 2002; Reddy et al. 2003; Acharya et al. 2006; Chavarria-Soley et al. 2006; Vincent et al. 2006; Chitsazian et al. 2007; Dimasi et al. 2007; Kumar et al. 2007; Suri et al. 2009; Tanwar et al. 2009; Pasutto et al. 2010; Azmanov et al. 2011; Prokudin et al. 2014). The p.Arg368His variant was also found in a homozygous state in two unaffected individuals and in a compound heterozygous state in ten self-reported unaffected individuals (Bejjani et al. 2000; Suri et al. 2009). The p.Arg368His variant was reported in a heterozygous state in five of 1030 controls and is also reported at a frequency of 0.030660 in the South Asian population of the Exome Aggregation Consortium. This database also includes thirteen homozygotes. In vitro functional studies showed that the variant demonstrated reduced enzymatic activity (Pasutto et al. 2010; Mookherjee et al. 2012). Expression of the variant protein in E. coli resulted in approximately one-sixth of the amount of stable protein compared to wild type and severely reduced metabolism of all substrates tested (Choudhary et al. 2008). While the p.Arg368His variant shows a strong association with disease, the presence of the variant in unaffected individuals in a homozygous and compound heterozygous state, and the high frequency in the population database suggests the variant results in greatly reduced disease penetrance. However, based on the high number of patient cases and functional data, the p.Arg368His variant is classified as pathogenic for CYP1B1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001083921 SCV001020682 benign Congenital glaucoma 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000489962 SCV001152236 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000023146 SCV001162949 pathogenic Glaucoma 3, primary congenital, A criteria provided, single submitter clinical testing
Laboratory of Human Genetics,Universidade de São Paulo RCV000023146 SCV001251969 pathogenic Glaucoma 3, primary congenital, A 2020-05-22 criteria provided, single submitter research Our patient is a girl, heterozygous for a maternally inherited pathogenic missense variant (NM_000104.3:c.1103G>A; p.Arg368His) in the CYP1B1 gene, whose mutations are the most common cause of primary congenital glaucoma (Qashqai et al., 2018). However, this pathogenic variant alone is not sufficient to explain her phenotype, as glaucoma due to CYP1B1 mutations is typical of an autosomal recessive inheritance (Reis et al., 2016).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000023146 SCV001370059 uncertain significance Glaucoma 3, primary congenital, A 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3.
Broad Institute Rare Disease Group, Broad Institute RCV001258308 SCV001435257 uncertain significance Myopathy, centronuclear, 5 criteria provided, single submitter research The p.Arg368His variant in CYP1B1 has been identified in at least 13 individuals with primary congenital glaucoma and in multiple unaffected individuals (PMID: 10655546, 19793111, 25091052, 19643970), but has also been identified in >2% of South Asian chromosomes and 10 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg368His variant may impact protein function (PMID: 23028769, 19643970). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000844695 SCV001467890 uncertain significance not specified 2020-12-14 criteria provided, single submitter clinical testing Variant summary: CYP1B1 c.1103G>A (p.Arg368His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0058 in 247034 control chromosomes, predominantly at a frequency of 0.03 within the South Asian subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma phenotype (0.0043), suggesting that the variant may be a benign polymorphism found primarily in populations of South Asian origin. c.1103G>A has been reported in the literature in individuals affected with Primary Congenital Glaucoma, primary open angle glaucoma or anterior segment developmental anomalies including glaucoma in homozygous or compound heterozygous states with reduced penetrance (e.g. Bejjani_2000, Tanwar_2009, Kaur_2018, Patel_2019). These reports do not provide unequivocal conclusions about association of the variant with Primary Congenital Glaucoma. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Choudhary_2008, Pasutto_2010, Mookherjee_2012, Banerjee_2016). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=3, benign n=1, VUS n=5). In addition, p.R368C and p.R368L have been reported to associate with primary congenital glaucoma. In summary, although this variant was frequently found in control population, possibility of this variant being a pathogenic variant with low penetrance can not be ruled out. Therefore, the variant was classified as uncertain significance.
Genomic Medicine Lab, University of California San Francisco RCV000023146 SCV001572947 uncertain significance Glaucoma 3, primary congenital, A 2020-05-14 criteria provided, single submitter clinical testing
OMIM RCV000008178 SCV000028383 pathogenic Glaucoma, early-onset, digenic 2011-03-01 no assertion criteria provided literature only
OMIM RCV000023146 SCV000044437 pathogenic Glaucoma 3, primary congenital, A 2011-03-01 no assertion criteria provided literature only
Eye Genetics Research Group,Children's Medical Research Institute RCV000059335 SCV000087421 uncertain significance Congenital ocular coloboma 2012-03-30 no assertion criteria provided research
GenomeConnect, ClinGen RCV000709869 SCV000840205 not provided Glaucoma 3, primary congenital, A; Irido-corneo-trabecular dysgenesis no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07/06/2015 by Lab or GTR ID 1006. 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.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000023146 SCV000891496 uncertain significance Glaucoma 3, primary congenital, A 2017-12-30 no assertion criteria provided curation

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