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NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His) AND Hereditary spastic paraplegia 5A

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Oct 4, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000006477.7

Allele description [Variation Report for NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)]

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

Gene:
CYP7B1:cytochrome P450 family 7 subfamily B member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
8q12.3
Genomic location:
Preferred name:
NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)
HGVS:
  • NC_000008.11:g.64596913C>T
  • NG_008338.2:g.206879G>A
  • NM_001324112.2:c.1234-7069G>A
  • NM_004820.5:c.1250G>AMANE SELECT
  • NP_004811.1:p.Arg417His
  • NC_000008.10:g.65509470C>T
  • NM_004820.3:c.1250G>A
  • NM_004820.4:c.1250G>A
  • O75881:p.Arg417His
Protein change:
R417H; ARG417HIS
Links:
UniProtKB: O75881#VAR_044385; OMIM: 603711.0004; dbSNP: rs121908611
NCBI 1000 Genomes Browser:
rs121908611
Molecular consequence:
  • NM_001324112.2:c.1234-7069G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_004820.5:c.1250G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary spastic paraplegia 5A (SPG5A)
Synonyms:
SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; Spastic paraplegia 5A; Autosomal recessive spastic paraplegia
Identifiers:
MONDO: MONDO:0010047; MedGen: C1849115; Orphanet: 100986; OMIM: 270800

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000026660OMIM
no assertion criteria provided
Pathogenic
(Jun 1, 2009) 		germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000967608Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Oct 4, 2018) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing

Citations

PubMed

Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity.

Hentati A, Pericak-Vance MA, Hung WY, Belal S, Laing N, Boustany RM, Hentati F, Ben Hamida M, Siddique T.

Hum Mol Genet. 1994 Aug;3(8):1263-7.

PubMed [citation]
PMID:
7987300

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.

Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Maréchal L, Fontaine B, Guimarães J, Isidor B, Chazouillères O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, et al.

Brain. 2009 Jun;132(Pt 6):1589-600. doi: 10.1093/brain/awp073. Epub 2009 May 12.

PubMed [citation]
PMID:
19439420
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000026660.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In affected members of 2 consanguineous Tunisian families with spastic paraplegia-5A (SPG5A; 270800) reported by Hentati et al. (1994), Tsaousidou et al. (2008) identified a homozygous 1250G-A transition in exon 6 of the CYP7B1 gene, resulting in an arg417-to-his (R417H) substitution.

Goizet et al. (2009) identified a homozygous R417H mutation in affected members of a family with SPG5A and in a patient with sporadic disease. Another family was compound heterozygous for R417H and F470I (603711.0008). Patients who were homozygous for the mutation presented a pure SPG, with mild to moderate lower limb involvement and decreased vibratory sensation. Some patients showed mild upper limb weakness.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967608.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (7)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Oct 13, 2024