ClinVar Miner

Submissions for variant NM_000103.4(CYP19A1):c.1263+1G>T

dbSNP: rs2031075939
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001196822 SCV001367455 likely pathogenic Aromatase deficiency 2020-02-13 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
3billion RCV001196822 SCV002572532 likely pathogenic Aromatase deficiency 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant on the canonical splice site is predicted to alter splicing, resulting in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. The homozygous variant has been reported to be associated with CYP19A1-related disorder (ClinVar ID: VCV000930859). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003558753 SCV004297265 pathogenic not provided 2023-08-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CYP19A1 protein in which other variant(s) (p.Arg435Cys) have been determined to be pathogenic (PMID: 8265607, 17164303, 23329769, 27256151). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 930859). Disruption of this splice site has been observed in individuals with aromatase deficiency (PMID: 29324451, 33108086). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the CYP19A1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

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