ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 577 of the POR protein (p.Leu577Pro). This variant is present in population databases (rs56256515, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440188). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Published functional studies demonstrate this variant results in reduced stability, reduced kinase activity, and enzymatic activity of drug-metabolizing cytochrome P450s (PMID: 38136599); 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: 17827787, 23353702, 27439448, 18551037, 27488389, 18216718, 27729266, 24847272, 27271371, 19374516, 18455494, 38136599)

Variant summary: POR c.1721T>C (p.Leu574Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 194968 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POR causing Congenital Adrenal Hyperplasia (0.00053 vs 0.00091), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1721T>C in individuals affected with Congenital Adrenal Hyperplasia has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in moderately reduced enzymatic activity (Rojas Velazquez_2023). The following publication has been ascertained in the context of this evaluation (PMID: 38136599). ClinVar contains an entry for this variant (Variation ID: 440188). Based on the evidence outlined above, the variant was classified as uncertain significance.

The POR p.L577P variant was identified in dbSNP (ID: rs56256515) and ClinVar (classified as uncertain significance by ARUP Laboratories). The variant was identified in control databases in 120 of 226358 chromosomes at a frequency of 0.0005301 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 112 of 99994 chromosomes (freq: 0.00112), Other in 2 of 6178 chromosomes (freq: 0.000324), African in 2 of 19524 chromosomes (freq: 0.000102), Latino in 3 of 29400 chromosomes (freq: 0.000102) and European (Finnish) in 1 of 20572 chromosomes (freq: 0.000049), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.L577 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional analysis demonstrated decreased POR activity from the p.L577P variant compared to wildtype (Hart_2008_PMID:18216718). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.