NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu) AND Spastic paraplegia 77, autosomal recessive

Clinical significance:Uncertain significance (Last evaluated: Nov 8, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000578164.2

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]

Condition(s)

Name:
Spastic paraplegia 77, autosomal recessive (SPG77)
Identifiers:
MONDO: MONDO:0014882; MedGen: C4310750; OMIM: 617046

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000680039OMIMno assertion criteria providedPathogenic
(Jan 30, 2018)
germlineliterature only

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

SCV001526168Baylor Geneticscriteria provided, single submitter
Uncertain significance
(Nov 8, 2018)
paternalclinical testing

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

Summary from all submissions

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

Citations

PubMed

New insights into the phenotype of FARS2 deficiency.

Vantroys E, Larson A, Friederich M, Knight K, Swanson MA, Powell CA, Smet J, Vergult S, De Paepe B, Seneca S, Roeyers H, Menten B, Minczuk M, Vanlander A, Van Hove J, Van Coster R.

Mol Genet Metab. 2017 Dec;122(4):172-181. doi: 10.1016/j.ymgme.2017.10.004. Epub 2017 Oct 12.

PubMed [citation]
PMID:
29126765
PMCID:
PMC5734183

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, SCV000680039.1

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

Description

In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046), Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene: a c.1082C-T transition (c.1082C-T, NM_006567.4) in exon 6, resulting in a pro361-to-leu (P361L) substitution in the anticodon binding domain, in both probands, combined with a c.461C-T transition in exon 2, resulting in an ala154-to-val (A154V; 611592.0009) substitution in the catalytic domain, in proband 1, and a 3-bp deletion (c.521_523delTGG), resulting in deletion of val174 (611592.0010) in the catalytic domain, in proband 2. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The P361L and A154V had a prevalence of 15/60,675 and 2/60,594, respectively, in the ExAC database, whereas V174del was not found in ExAC. Compared with normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes: complex IV in proband 1 and complex I in proband 2.

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

From Baylor Genetics, SCV001526168.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Jul 13, 2021

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