Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000426000 | SCV000346001 | uncertain significance | not provided | 2016-09-23 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000426000 | SCV000521347 | likely pathogenic | not provided | 2016-09-09 | criteria provided, single submitter | clinical testing | The P198L variant in the AKR1D1 gene has been reported previously in the homozygous state in an individual with neonatal onset cholestatic liver disease (Lemonde et al., 2003). HEK293 cells transiently transfected with the P198L variant showed reduced protein expression and decreased protein stability compared to wild type, as well as displayed no detectable 5b-reductase enzyme activity using testosterone as substrate (Drury et al., 2010). The P198L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P198L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. The P198L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000005705 | SCV004122873 | likely pathogenic | Congenital bile acid synthesis defect 2 | 2023-10-13 | criteria provided, single submitter | clinical testing | Variant summary: AKR1D1 c.593C>T (p.Pro198Leu) results in a non-conservative amino acid change located in the NADP-dependent oxidoreductase domain (IPR023210) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251442 control chromosomes (gnomAD). c.593C>T has been reported in the literature in individuals affected with neonatal onset cholestatic/AKR1D1 deficiency (examples: Lemonde_2003, Palmero_2008, Zhang_2019, Wang_2019). These data indicate that the variant may be associated with disease. Multiple studies have shown mutant P198L showed reduced protein expression and decreased protein stability compared to wild type, as well as displayed no detectable 5b-reductase enzyme activity using testosterone as a substrate (examples: Drury_2010 and Mindnich_2011). The following publications have been ascertained in the context of this evaluation (PMID: 12970144, 30809085, 31450232, 21185810, 18243262, 20522910). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
OMIM | RCV000005705 | SCV000025887 | pathogenic | Congenital bile acid synthesis defect 2 | 2003-10-01 | no assertion criteria provided | literature only |