ClinVar Miner

Submissions for variant NM_000398.7(CYB5R3):c.806C>T (p.Pro269Leu)

gnomAD frequency: 0.00001  dbSNP: rs754251915
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001270756 SCV001451506 likely pathogenic Deficiency of cytochrome-b5 reductase 2019-03-18 criteria provided, single submitter clinical testing The CYB5R3 c.806C>T (p.Pro269Leu) variant is a missense variant that has been reported in two studies, in which it is found in a total of 59 individuals with congenital methemoglobinemia type I, including at least in 16 in a homozygous state (Puzyrev and Maximova 2008; Burtseva et al. 2017). The p.Pro269Leu is a founder variant in the Yakut population with a frequency of heterozygous carriers of about 1% in the entire population of the Republic of Sakha and 7% in the indigenous Yakut population (Galeeva et al. 2013; Burtseva et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000119 in the Latino population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Pro269Leu variant is classified as likely pathogenic for congenital methemoglobinemia.
Invitae RCV002541655 SCV003444348 uncertain significance not provided 2022-08-09 criteria provided, single submitter clinical testing 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 989273). This variant has not been reported in the literature in individuals affected with CYB5R3-related conditions. This variant is present in population databases (rs754251915, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 269 of the CYB5R3 protein (p.Pro269Leu).

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