Submissions for variant NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)

gnomAD frequency: 0.00006  dbSNP: rs121908611

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206595	SCV000261512	pathogenic	Spastic paraplegia	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 417 of the CYP7B1 protein (p.Arg417His). This variant is present in population databases (rs121908611, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 18252231, 19439420, 22384504). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6103). 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 CYP7B1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg417 amino acid residue in CYP7B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19439420, 21567895, 24658845). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000329074	SCV000330028	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing	The R417H variant in the CYP7B1 gene has been reported previously multiple times in the homozygous and compound heterozygous state in individuals with spastic paraplegia (Tsaousidou et al., 2008; Goizet et al., 2009; Marelli et al., 2017). Additional studies have also indicated that pathogenic variants involving R417 may impair catalytic function and indirectly affect ligand binding (Siam et al., 2012). The R417H variant is observed in 2/18838 (0.003%) alleles from individuals of Asian background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at the same position (R417C and R417G) have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014). We interpret R417H as a pathogenic variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000006477	SCV000967608	likely pathogenic	Hereditary spastic paraplegia 5A	2018-10-04	criteria provided, single submitter	clinical testing	The p.Arg417His variant in CYP7B1 has been reported in 6 individuals with spasti c paraplegia and two young children with oxysterol 7a-hydroxylase deficiency, an d segregated with spastic paraplegia in 10 affected relatives from 4 families (T saousidou 2008, Goizet 2009, Mizuochi 2011, Noreau 2012, Dai 2014). This variant has been identified in 2/18838 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 6103). Molecular modeling studies, computational prediction tool s, and conservation analysis suggest that the p.Arg417His variant may impact the protein, though this information is not predictive enough to determine pathogen icity (Siam 2012). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classifi ed as likely pathogenic for autosomal recessive spastic paraplegia type 5. ACMG/ AMP criteria applied: PM3_Strong, PM2, PP1_Moderate, PP3.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847591	SCV002104547	pathogenic	Hereditary spastic paraplegia	2020-10-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000329074	SCV004229199	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with spastic paraplegia in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
PreventionGenetics, part of Exact Sciences	RCV003894794	SCV004714941	pathogenic	CYP7B1-related disorder	2024-02-27	criteria provided, single submitter	clinical testing	The CYP7B1 c.1250G>A variant is predicted to result in the amino acid substitution p.Arg417His. This variant was reported in the homozygous state in an individual with hereditary spastic paraplegia (Family 2, Tsaousidou et al 2008. PubMed ID: 18252231). This variant was also identified in the heterozygous state, and interpreted as pathogenic, in three individuals in a study utiziling exome sequencing for preconception carrier screening (Supplementary Table 1, Capalbo A et al 2019. PubMed ID: 31589614). Comparative modeling of CYP7B1 shows that the R417 amino acid resides in the meander region, which is the conserved PERF region, and suggests that any variant involving the R417 amino acid would be predicted to severely affect enzyme function (Siam A et al 2011. PubMed ID: 21541746). In addition, other variants impact the R417 amino acids have also been reported in individuals with hereditary spastic paraplegia (Goizet et al. 2009. PubMed ID: 19439420; Cao et al. 2011. PubMed ID: 21452256). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. Taken together, we interpret this variant as pathogenic.
OMIM	RCV000006477	SCV000026660	pathogenic	Hereditary spastic paraplegia 5A	2009-06-01	no assertion criteria provided	literature only