NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu) AND Combined oxidative phosphorylation deficiency 14

Clinical significance:Likely pathogenic (Last evaluated: Oct 5, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000525331.8

Allele description [Variation Report for NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu)]

NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu)

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.1082C>T (p.Pro361Leu)
Other names:
p.P361L:CCG>CTG
HGVS:
  • NC_000006.12:g.5613185C>T
  • NG_033003.1:g.356835C>T
  • NG_033003.2:g.356835C>T
  • NM_001318872.1:c.1082C>T
  • NM_006567.5:c.1082C>TMANE SELECT
  • NP_001305801.1:p.Pro361Leu
  • NP_006558.1:p.Pro361Leu
  • NC_000006.11:g.5613418C>T
  • NM_006567.3:c.1082C>T
  • NM_006567.4:c.1082C>T
Protein change:
P361L; PRO361LEU
Links:
OMIM: 611592.0008; dbSNP: rs751459058
NCBI 1000 Genomes Browser:
rs751459058
Molecular consequence:
  • NM_001318872.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006567.5:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000652835Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 5, 2020)
germlineclinical testing

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

SCV000680227Institute of Human Genetics, Klinikum rechts der Isarno assertion criteria provided
Pathogenic
(Nov 16, 2017)
maternalclinical testing

Citation Link,

SCV000845716Wong 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 providedmaternalyes1not providednot provided1not providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Two types of recessive hereditary spastic paraplegia in Roma patients in compound heterozygous state; no ethnically prevalent variant found.

Meszarosova AU, Seeman P, Jencik J, Drabova J, Cibochova R, Stellmachova J, Safka Brozkova D.

Neurosci Lett. 2020 Mar 16;721:134800. doi: 10.1016/j.neulet.2020.134800. Epub 2020 Jan 30.

PubMed [citation]
PMID:
32007496

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000652835.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline with leucine at codon 361 of the FARS2 protein (p.Pro361Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs751459058, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of FARS2-related conditions (PMID: 29126765, 32007496). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214335). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Institute of Human Genetics, Klinikum rechts der Isar, SCV000680227.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyes1bloodnot provided1not providednot providednot provided

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000845716.1

#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: Jul 13, 2021

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