rs747965749
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_183075.3(CYP2U1):c.1376C>T(p.Pro459Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,611,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P459P) has been classified as Likely benign.
Frequency
Consequence
NM_183075.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP2U1 | NM_183075.3 | c.1376C>T | p.Pro459Leu | missense_variant | 4/5 | ENST00000332884.11 | |
LOC107986298 | XR_001741784.2 | n.204+29283G>A | intron_variant, non_coding_transcript_variant | ||||
CYP2U1 | XM_005262717.2 | c.1430C>T | p.Pro477Leu | missense_variant | 4/5 | ||
CYP2U1 | XM_005262720.2 | c.740C>T | p.Pro247Leu | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP2U1 | ENST00000332884.11 | c.1376C>T | p.Pro459Leu | missense_variant | 4/5 | 1 | NM_183075.3 | P1 | |
CYP2U1-AS1 | ENST00000656249.1 | n.80+29283G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152024Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 249996Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135122
GnomAD4 exome AF: 0.0000678 AC: 99AN: 1459156Hom.: 0 Cov.: 30 AF XY: 0.0000661 AC XY: 48AN XY: 725866
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152024Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74234
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 12, 2022 | PM2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2023 | 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) - |
Hereditary spastic paraplegia 56 Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | 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 - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | 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. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 14, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at