Submissions for variant NM_001395413.1(POR):c.1255T>G (p.Trp419Gly)

gnomAD frequency: 0.00014  dbSNP: rs536353066

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812518	SCV002048999	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing	The POR c.1264T>G, p.Trp422Gly variant (rs536353066), to our knowledge, has not been described in an individual with skeletal abnormalities, but has been described in an individual with a disorder of sex development (Camats 2018). The variant is found in the European (non-Finnish) population with an allele frequency of 0.01% (12/125,514 alleles) in the Genome Aggregation Database. The tryptophan at codon 422 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.713). Due to limited information, the clinical significance of the p.Trp422Gly variant is uncertain at this time. References: Camats N et al. Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin? Eur J Hum Genet. Eur J Hum Genet. 2018 Sep;26(9):1329-1338.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869475	SCV002213055	uncertain significance	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 422 of the POR protein (p.Trp422Gly). This variant is present in population databases (rs536353066, gnomAD 0.009%). 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: 1330930). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801053	SCV005422308	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: POR c.1255T>G (p.Trp419Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 236554 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POR causing Congenital Adrenal Hyperplasia (4.7e-05 vs 0.00091), allowing no conclusion about variant significance. c.1255T>G has been reported in the literature in individuals affected with a disorder of sex development. These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29891883). ClinVar contains an entry for this variant (Variation ID: 1330930). Based on the evidence outlined above, the variant was classified as uncertain significance.