Submissions for variant NM_000104.4(CYP1B1):c.155C>T (p.Pro52Leu)

gnomAD frequency: 0.00030  dbSNP: rs201824781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000349391	SCV000339659	uncertain significance	not provided	2016-03-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139674	SCV001299850	uncertain significance	Glaucoma 3A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001139675	SCV001299851	uncertain significance	Irido-corneo-trabecular dysgenesis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000349391	SCV001823117	uncertain significance	not provided	2020-03-12	criteria provided, single submitter	clinical testing	Reported in two individuals of Italian ancestry with congenital glaucoma who were compound heterozygous for the P52L variant and another missense variant (Giuffre et al., 2011); Reported as a single heterozygous variant in two unrelated individuals, one with open angle glaucoma presenting at age 6, and the other with primary congenital glaucoma; however, this variant has also been observed in an older adult without visual defects, and in siblings and a parent of the patient with primary congenital glaucoma, leading some authors to suggest that this variant may demonstrate incomplete penetrance or that it may be rare variant unrelated to the phenotype (Lopez-Garrido, et al., 2006, Campos-Mollo et al., 2009; Pasutto et al., 2010); Published functional studies have demonstrated that P52L results in reduction but not absence of enzymatic activity as compared to wild-type, suggesting it may be a hypomorphic allele (Jeannot et al., 2007; Pasutto et al., 2010; Campos-Mollo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 17363580, 27243976, 21815720, 16862072, 19234632, 30484747, 19643970)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155038	SCV003844592	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: CYP1B1 c.155C>T (p.Pro52Leu) 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 0.00032 in 210080 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.155C>T has been reported in the literature in several individuals affected with Primary Congenital Glaucoma and primary open angle glaucoma (e.g., Campos-Mollo_2009, Pasutto_2010, Giuffre_2011, Svidnicki_2018). However, the variant has also been reported in unaffected individuals, including a homozygous individual with epileptic encephalopathy but no evidence of anterior chamber ocular abnormality or glaucoma (e.g., Palmer_2016, Lopez-Garrido_2006). These reports suggest the variant represents a hypomorphic allele that may display incomplete penetrance, and therefore these reports do not provide unequivocal conclusions about association of the variant with Primary Congenital Glaucoma. Multiple publications also report experimental evidence evaluating an impact on protein function, finding that the variant protein displays drastically reduced enzymatic activity (ranging from ~0% to 40% of wild-type activity) as well as reduced protein stability (e.g., Jeannot_2007, Campos-Mollo_2009, Pasutto_2010, Lopez-Garrido_2010). The following publications have been ascertained in the context of this evaluation (PMID: 19234632, 21815720, 17363580, 19793111, 16862072, 27270415, 19643970, 30484747). Four ClinVar submitters (evaluation after 2014) have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000023148	SCV000044439	pathogenic	Glaucoma, primary open angle, juvenile-onset	2010-01-01	no assertion criteria provided	literature only