NM_024306.5(FA2H):c.205C>T (p.His69Tyr) AND Spastic paraplegia

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 13, 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:: RCV000529889.6

Allele description

NM_024306.5(FA2H):c.205C>T (p.His69Tyr)

Genes:

LOC130059394:ATAC-STARR-seq lymphoblastoid silent region 7701 [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.205C>T (p.His69Tyr)

HGVS:

NC_000016.10:g.74774551G>A
NG_017070.1:g.5281C>T
NM_024306.5:c.205C>TMANE SELECT
NP_077282.3:p.His69Tyr
NC_000016.9:g.74808449G>A
NM_024306.4:c.205C>T

Protein change:

H69Y

Links:

dbSNP: rs1057519235

NCBI 1000 Genomes Browser:

rs1057519235

Molecular consequence:

NM_024306.5:c.205C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Spastic paraplegia
Identifiers:: MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000629520	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31135052, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629520

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

Rattay TW, Lindig T, Baets J, Smets K, Deconinck T, Söhn AS, Hörtnagel K, Eckstein KN, Wiethoff S, Reichbauer J, Döbler-Neumann M, Krägeloh-Mann I, Auer-Grumbach M, Plecko B, Münchau A, Wilken B, Janauschek M, Giese AK, De Bleecker JL, Ortibus E, Debyser M, Lopez de Munain A, et al.

Brain. 2019 Jun 1;142(6):1561-1572. doi: 10.1093/brain/awz102.

PubMed [citation]

PMID:: 31135052
PMCID:: PMC6536916

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000629520.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 FA2H protein function. ClinVar contains an entry for this variant (Variation ID: 374759). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31135052). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 69 of the FA2H protein (p.His69Tyr).

#	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: Feb 20, 2024

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