ClinVar Miner

Submissions for variant NM_000104.4(CYP1B1):c.535del (p.Ala179fs)

dbSNP: rs771076928
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627426 SCV000748424 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The c.535delG variant in the CYP1B1 gene has been reported previously in association with autosomal recessive primary congenital glaucoma, and has been reported as a founder mutation in the Moroccan population (Belmouden et al., 2002; Gronskov et al., 2016). This variant causes a frameshift starting with codon Alanine 179, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ala179ArgfsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.535delG variant is observed in 4/26120 (0.015%) alleles from individuals of Latino background and 7/182840 (0.004%) global alleles in large population cohorts, with no homozygotes identified (Lek et al., 2016). We interpret c.535delG as a pathogenic variant.
Invitae RCV000631367 SCV000752402 pathogenic Congenital glaucoma 2023-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala179Argfs*18) in the CYP1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP1B1 are known to be pathogenic (PMID: 9097971, 9497261, 19234632). This variant is present in population databases (rs771076928, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with open-angle glaucoma, and primary congenital glaucoma (PMID: 12372064, 19234632, 23922489, 27272408, 27777502, 27820421). It has also been observed to segregate with disease in related individuals. This variant is also known as c.4339delG, c.906delG, c.534_535delG (p.Ala179ArgfsX16). ClinVar contains an entry for this variant (Variation ID: 523943). For these reasons, this variant has been classified as Pathogenic.
3billion RCV001250447 SCV002058588 pathogenic Glaucoma 3A 2022-01-03 criteria provided, single submitter clinical testing Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000523943, PMID:12372064).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002491346 SCV002792131 pathogenic Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6 2021-08-30 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV001250447 SCV003806852 pathogenic Glaucoma 3A 2023-01-31 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong
PreventionGenetics, part of Exact Sciences RCV004533300 SCV004113890 pathogenic CYP1B1-related disorder 2023-06-07 criteria provided, single submitter clinical testing The CYP1B1 c.535delG variant is predicted to result in a frameshift and premature protein termination (p.Ala179Argfs*18). This variant was reported in the homozygous or compound heterozygous state to be causative for primary congenital glaucoma (described as 4339delG, Bouyacoub et al. 2014. PubMed ID: 24942078; Cardoso et al. 2015. PubMed ID: 25952714; García-Antón et al. 2017. PubMed ID: 28448622). This variant is reported in 0.019% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-38301996-GC-G). Frameshift variants in CYP1B1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV001449669 SCV004215462 pathogenic Anterior segment dysgenesis 6 2023-10-09 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000627426 SCV004235472 pathogenic not provided 2023-06-02 criteria provided, single submitter clinical testing
OMIM RCV001250447 SCV000028382 pathogenic Glaucoma 3A 2002-10-01 no assertion criteria provided literature only
Institute of Medical Molecular Genetics, University of Zurich RCV001250447 SCV001424835 pathogenic Glaucoma 3A 2019-08-01 no assertion criteria provided research
OMIM RCV001449669 SCV001652918 pathogenic Anterior segment dysgenesis 6 2002-10-01 no assertion criteria provided literature only

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