NM_006567.5(FARS2):c.986T>C (p.Ile329Thr) AND Combined oxidative phosphorylation deficiency 14

Clinical significance:Likely pathogenic (Last evaluated: Jun 13, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000033045.4

Allele description [Variation Report for NM_006567.5(FARS2):c.986T>C (p.Ile329Thr)]

NM_006567.5(FARS2):c.986T>C (p.Ile329Thr)

Gene:
FARS2:phenylalanyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p25.1
Genomic location:
Preferred name:
NM_006567.5(FARS2):c.986T>C (p.Ile329Thr)
HGVS:
  • NC_000006.12:g.5545261T>C
  • NG_033003.1:g.288911T>C
  • NG_033003.2:g.288911T>C
  • NM_001318872.1:c.986T>C
  • NM_006567.5:c.986T>CMANE SELECT
  • NP_001305801.1:p.Ile329Thr
  • NP_006558.1:p.Ile329Thr
  • NC_000006.11:g.5545494T>C
  • NM_006567.4:c.986T>C
  • O95363:p.Ile329Thr
Protein change:
I329T; ILE329THR
Links:
UniProtKB: O95363#VAR_069488; OMIM: 611592.0002; dbSNP: rs397514611
NCBI 1000 Genomes Browser:
rs397514611
Molecular consequence:
  • NM_001318872.1:c.986T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006567.5:c.986T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined oxidative phosphorylation deficiency 14 (COXPD14)
Identifiers:
MONDO: MONDO:0013986; MedGen: C3554168; Orphanet: 319519; OMIM: 614946

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000056825OMIMno assertion criteria providedPathogenic
(Oct 15, 2012)
germlineliterature only

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

SCV000845715Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Jun 13, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.

Elo JM, Yadavalli SS, Euro L, Isohanni P, Götz A, Carroll CJ, Valanne L, Alkuraya FS, Uusimaa J, Paetau A, Caruso EM, Pihko H, Ibba M, Tyynismaa H, Suomalainen A.

Hum Mol Genet. 2012 Oct 15;21(20):4521-9. Epub 2012 Jul 23.

PubMed [citation]
PMID:
22833457

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, SCV000056825.2

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

Description

In 2 Finnish sibs with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Elo et al. (2012) identified compound heterozygosity for 2 mutations in the FARS2 gene: a 986T-C transition in exon 5 resulting in an ile329-to-thr (I329T) substitution, and a 1172A-T transversion in exon 6 resulting in an asp391-to-val (D391V; 611592.0003) substitution. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 400 Finnish control chromosomes or in the 1000 Genomes Project database. Both mutations occurred at highly conserved residues. The ile329 residue is part of the ATP-binding site in the aminoacylation domain, whereas asp391 is in the anticodon stem-binding domain. In vitro functional expression studies in E. coli indicated that the I329T mutation resulted in a 4-fold decrease in the catalytic activity of amino acid activation due to a decreased affinity for ATP. The D391V mutation was predicted to result in a decrease in phe binding, causing a decrease in aminoacylation activity. Both mutations also caused decreased stabilization of the proteins, resulting in a decrease in overall charging capacity.

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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000845715.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 8, 2020

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