ClinVar Miner

Submissions for variant NM_183075.3(CYP2U1):c.1376C>T (p.Pro459Leu)

gnomAD frequency: 0.00005  dbSNP: rs747965749
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000692719 SCV000820557 pathogenic Spastic paraplegia 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 459 of the CYP2U1 protein (p.Pro459Leu). This variant is present in population databases (rs747965749, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of CYP2U1-related conditions (PMID: 36166872; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571544). 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 expected to disrupt CYP2U1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Paris Brain Institute, Inserm - ICM RCV001391446 SCV001451140 pathogenic Hereditary spastic paraplegia 56 criteria provided, single submitter clinical testing
GeneDx RCV001570056 SCV001794256 pathogenic not provided 2023-06-20 criteria provided, single submitter clinical testing Reported with a second variant (phase unknown) in a patient with hereditary spastic paraplegia in published literature (Leeson et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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: 36166872)
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001849057 SCV002104518 uncertain significance Hereditary spastic paraplegia 2020-01-14 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001570056 SCV002568128 uncertain significance not provided 2022-05-12 criteria provided, single submitter clinical testing PM2, PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001391446 SCV002768821 uncertain significance Hereditary spastic paraplegia 56 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 56 (MIM#615030). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_183075.3(CYP2U1): c.1462C>T; p.(Arg488Trp)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS# 20W000940). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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