NM_024306.5(FA2H):c.703C>T (p.Arg235Cys) AND Hereditary spastic paraplegia 35

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Dec 14, 2022
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:: RCV000023855.10

Allele description [Variation Report for NM_024306.5(FA2H):c.703C>T (p.Arg235Cys)]

NM_024306.5(FA2H):c.703C>T (p.Arg235Cys)

Gene:

FA2H:fatty acid 2-hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q23.1

Genomic location:

Preferred name:

NM_024306.5(FA2H):c.703C>T (p.Arg235Cys)

HGVS:

NC_000016.10:g.74719071G>A
NG_017070.1:g.60761C>T
NM_024306.5:c.703C>TMANE SELECT
NP_077282.3:p.Arg235Cys
NC_000016.9:g.74752969G>A
NM_024306.4:c.703C>T
Q7L5A8:p.Arg235Cys

Protein change:

R235C; ARG235CYS

Links:

UniProtKB: Q7L5A8#VAR_064621; OMIM: 611026.0003; dbSNP: rs387907039

NCBI 1000 Genomes Browser:

rs387907039

Molecular consequence:

NM_024306.5:c.703C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary spastic paraplegia 35
Synonyms:: Leukodystrophy, dysmyelinating, and spastic paraparesis with or without dystonia; Spastic paraplegia 35; Spastic paraplegia 35, autosomal recessive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012866; MedGen: C3496228; Orphanet: 171629; OMIM: 612319

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045146	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000891500	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	no assertion criteria provided	Likely pathogenic (Jun 12, 2024)	unknown	curation
SCV003831176	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000045146

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 2010)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000891500

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

no assertion criteria provided

Likely pathogenic
(Jun 12, 2024)

unknown

curation

SCV003831176

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 14, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).

Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH.

Hum Mutat. 2010 Apr;31(4):E1251-60. doi: 10.1002/humu.21205.

PubMed [citation]

PMID:: 20104589

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000045146.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a consanguineous Omani family with complicated autosomal recessive spastic paraplegia-35 (SPG35; 612319), Dick et al. (2010) identified a homozygous 703C-T transition in exon 5 of the FA2H gene, resulting in an arg235-to-cys (R235C) substitution. The mutation was not found in 700 control chromosomes. In vitro functional expression studies showed that the mutation resulted in a reduction in hydroxylated ceramides to 60-80% of wildtype.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, SCV000891500.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003831176.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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