Submissions for variant NM_183075.3(CYP2U1):c.1462C>T (p.Arg488Trp)

gnomAD frequency: 0.00003  dbSNP: rs141431913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814689	SCV000955108	pathogenic	Spastic paraplegia	2023-05-31	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with CYP2U1-related conditions (PMID: 23176821, 33107650). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYP2U1 function (PMID: 29034544). 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. ClinVar contains an entry for this variant (Variation ID: 39504). This variant is present in population databases (rs141431913, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 488 of the CYP2U1 protein (p.Arg488Trp).
Paris Brain Institute, Inserm - ICM	RCV000032700	SCV001451141	pathogenic	Hereditary spastic paraplegia 56		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847627	SCV002104519	likely pathogenic	Hereditary spastic paraplegia	2018-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002264909	SCV002546756	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced protein expression and absent enzyme activity (Durand et al., 2018; Legrand et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27292318, 33107650, 23176821, 29034544, 34546337, 36166872, 34426522)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032700	SCV002768822	likely pathogenic	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 likely pathogenic. 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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg488Gly): 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional heme-binding domain, two residues from the axial cysteine ligand (PMIDs: 14660610, 29034544). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been identified in two siblings with early-onset spastic paraplegia (PMID: 23176821). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant expression vector transfected into HEK293T cells demonstrated reduced protein expression and total loss of arachidonic acid hydroxylation activity compared to the wild type expression construct (PMID: 29034544). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS# 20W000939). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000032700	SCV000056463	pathogenic	Hereditary spastic paraplegia 56	2012-12-07	no assertion criteria provided	literature only