NM_006567.5(FARS2):c.467C>T (p.Thr156Met) AND Combined oxidative phosphorylation defect type 14

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000714948.10

Allele description [Variation Report for NM_006567.5(FARS2):c.467C>T (p.Thr156Met)]

NM_006567.5(FARS2):c.467C>T (p.Thr156Met)

Genes:

LOC126859565:CDK7 strongly-dependent group 2 enhancer GRCh37_chr6:5368745-5369944 [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.467C>T (p.Thr156Met)

HGVS:

NC_000006.12:g.5369037C>T
NG_033003.2:g.112687C>T
NM_001318872.2:c.467C>T
NM_001374875.1:c.467C>T
NM_001374876.1:c.467C>T
NM_001374877.1:c.467C>T
NM_001374878.1:c.467C>T
NM_001374879.1:c.467C>T
NM_001375257.1:c.467C>T
NM_001375258.1:c.467C>T
NM_001375259.1:c.-84-35505C>T
NM_001375260.1:c.-340-27596C>T
NM_006567.5:c.467C>TMANE SELECT
NP_001305801.1:p.Thr156Met
NP_001361804.1:p.Thr156Met
NP_001361805.1:p.Thr156Met
NP_001361806.1:p.Thr156Met
NP_001361807.1:p.Thr156Met
NP_001361808.1:p.Thr156Met
NP_001362186.1:p.Thr156Met
NP_001362187.1:p.Thr156Met
NP_006558.1:p.Thr156Met
NC_000006.11:g.5369270C>T
NM_006567.3:c.467C>T
NM_006567.4:c.467C>T

Protein change:

T156M

Links:

dbSNP: rs146988468

NCBI 1000 Genomes Browser:

rs146988468

Molecular consequence:

NM_001375259.1:c.-84-35505C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001375260.1:c.-340-27596C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001318872.2:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374875.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374876.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374877.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374878.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374879.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375257.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375258.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006567.5:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined oxidative phosphorylation defect type 14
Synonyms:: Combined oxidative phosphorylation deficiency 14
Identifiers:: MONDO: MONDO:0013986; MedGen: C4755312; Orphanet: 319519; OMIM: 614946

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000845724	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 13, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27652284, 25741868
SCV001234219	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27652284, 33972171, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000845724

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 13, 2018)

germline

clinical testing

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

SCV001234219

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

de Kovel CG, Brilstra EH, van Kempen MJ, Van't Slot R, Nijman IJ, Afawi Z, De Jonghe P, Djémié T, Guerrini R, Hardies K, Helbig I, Hendrickx R, Kanaan M, Kramer U, Lehesjoki AE, Lemke JR, Marini C, Mei D, Møller RS, Pendziwiat M, Stamberger H, Suls A, et al.

Mol Genet Genomic Med. 2016 Sep;4(5):568-80. doi: 10.1002/mgg3.235.

PubMed [citation]

PMID:: 27652284
PMCID:: PMC5023942

See all PubMed Citations (4)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000845724.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234219.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 156 of the FARS2 protein (p.Thr156Met). This variant is present in population databases (rs146988468, gnomAD 0.06%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 27652284, 33972171). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 587677). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FARS2 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 20, 2024

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