Submissions for variant NM_183075.3(CYP2U1):c.343G>A (p.Gly115Ser)

gnomAD frequency: 0.00001  dbSNP: rs766889023

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379753	SCV001577613	likely pathogenic	Spastic paraplegia	2021-02-22	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 29034544). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces glycine with serine at codon 115 of the CYP2U1 protein (p.Gly115Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs766889023, ExAC 0.01%). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847253	SCV002104522	likely pathogenic	Hereditary spastic paraplegia	2021-06-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002276241	SCV002563818	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004576988	SCV005060945	likely pathogenic	Hereditary spastic paraplegia 56		criteria provided, single submitter	clinical testing	The observed missense variant c.343G>A (p.Gly115Ser) in CYP2U1 gene has been reported previously in individuals affected with autosomal recessive spastic paraplegia (Durand et al. 2018). Experimental evidence shows conflicting data with a similar levels of protein expression for this variant as compared to the wild type, and a lack of 450nm absorbance peak as seen in the wild type (Durand et al. 2018). The p.Gly115Ser variant is present with an allele frequency of 0.001% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic / Likely Pathogenic. The amino acid change p.Gly115Ser in CYP2U1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 115 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Replacement of Glycine with a bulkier residue Serine, might lead to a steric clash between the side chain of this residue and that of the Pro61 residue located at the transmembrane helix (TMH) end that could destabilize the CYP2U1 protein and lead to a complete loss-of-function, explaining the lack of 450 nm peak in the UV-vis difference spectrum of this protein (Durand et al. 2018). For these reasons, this variant has been classified as Likely Pathogenic.