Submissions for variant NM_000104.4(CYP1B1):c.1390dup (p.Ser464fs)

dbSNP: rs777515179

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001885179	SCV002240388	pathogenic	Congenital glaucoma	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser464Phefs*14) in the CYP1B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the CYP1B1 protein. This variant is present in population databases (rs777515179, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CYP1B1-related conditions. This variant is also known as c.1385_1390insT (p.Ser464PhefsX12). ClinVar contains an entry for this variant (Variation ID: 1324202). This variant disrupts a region of the CYP1B1 protein in which other variant(s) (p.Ser464*) have been determined to be pathogenic (PMID: 24940937; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003313231	SCV004012748	likely pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Identified as p.Ser464PhefsX12 with a second CYP1B1 variant in an individual with primary congenital glaucoma in the published literature (PMID: 23922489); Frameshift variant predicted to result in protein truncation, as the last 80 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26689913, 23922489, 36995002)
Baylor Genetics	RCV003470910	SCV004215476	pathogenic	Anterior segment dysgenesis 6	2024-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801049	SCV005423231	pathogenic	Primary congenital glaucoma	2024-10-15	criteria provided, single submitter	clinical testing	Variant summary: CYP1B1 c.1390dupT (p.Ser464PhefsX14) results in a premature termination codon in the last exon, predicted to cause a truncation of the encoded protein, however, nonsense mediated decay is not expected to occur. The variant allele was found at a frequency of 8e-06 in 251452 control chromosomes. c.1390dupT has been reported in the literature in multiple compound heterozygous individuals affected with Primary Congenital Glaucoma, including patients with a bilateral phenotype (e.g. Cardoso_2015, Milla_2013). These data indicate that the variant may be associated with disease. At least one downstream pathogenic variant has been classified as Pathogenic by our lab and in ClinVar (c.1405C>T (p.Arg469Trp)), providing evidence that the region altered by the variant is critical to protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25952714, 23922489). ClinVar contains an entry for this variant (Variation ID: 1324202). Based on the evidence outlined above, the variant was classified as pathogenic.