The Y144C missense variant in the FARS2 gene has been identified through whole exome sequencing in the homozygous state in three siblings with mitochondrial encephalopathy (Shamseldin et al. 2012). Functional studies found that Y144C disrupts tRNA binding and stability of the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) protein leading to a decrease in tRNA charging capacity (Elo et al. 2012). The Y144C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y144C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant to be likely pathogenic. This finding is likely consistent with a diagnosis of combined oxidative phosphorylation deficiency-14 in this patient. However, this result could also be seen if the patient had one allele with the Y144C pathogenic variant and one allele that was partially missing or refractory to amplification.
ClinVar Genomic variation as it relates to human health
NM_006567.5(FARS2):c.431A>G (p.Tyr144Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006567.5(FARS2):c.431A>G (p.Tyr144Cys)
Variation ID: 39824 Accession: VCV000039824.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p25.1 6: 5369001 (GRCh38) [ NCBI UCSC ] 6: 5369234 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 7, 2024 Mar 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006567.5:c.431A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006558.1:p.Tyr144Cys missense NM_001318872.2:c.431A>G NP_001305801.1:p.Tyr144Cys missense NM_001374875.1:c.431A>G NP_001361804.1:p.Tyr144Cys missense NM_001374876.1:c.431A>G NP_001361805.1:p.Tyr144Cys missense NM_001374877.1:c.431A>G NP_001361806.1:p.Tyr144Cys missense NM_001374878.1:c.431A>G NP_001361807.1:p.Tyr144Cys missense NM_001374879.1:c.431A>G NP_001361808.1:p.Tyr144Cys missense NM_001375257.1:c.431A>G NP_001362186.1:p.Tyr144Cys missense NM_001375258.1:c.431A>G NP_001362187.1:p.Tyr144Cys missense NM_001375259.1:c.-84-35541A>G intron variant NM_001375260.1:c.-340-27632A>G intron variant NC_000006.12:g.5369001A>G NC_000006.11:g.5369234A>G NG_033003.2:g.112651A>G O95363:p.Tyr144Cys - Protein change
- Y144C
- Other names
- -
- Canonical SPDI
- NC_000006.12:5369000:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FARS2 | - | - |
GRCh38 GRCh37 |
329 | 612 | |
| LOC126859565 | - | - | - | GRCh38 | - | 207 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV000033044.15 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2014 | RCV000162158.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 22, 2016 | RCV000497519.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation deficiency 14
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005038812.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
|
|
|
Likely pathogenic
(Jun 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589666.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The Y144C missense variant in the FARS2 gene has been identified through whole exome sequencing in the homozygous state in three siblings with mitochondrial encephalopathy … (more)
The Y144C missense variant in the FARS2 gene has been identified through whole exome sequencing in the homozygous state in three siblings with mitochondrial encephalopathy (Shamseldin et al. 2012). Functional studies found that Y144C disrupts tRNA binding and stability of the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) protein leading to a decrease in tRNA charging capacity (Elo et al. 2012). The Y144C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y144C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant to be likely pathogenic. This finding is likely consistent with a diagnosis of combined oxidative phosphorylation deficiency-14 in this patient. However, this result could also be seen if the patient had one allele with the Y144C pathogenic variant and one allele that was partially missing or refractory to amplification. (less)
|
|
|
Pathogenic
(Jun 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation deficiency 14
Affected status: yes
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000845708.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation defect type 14
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001389842.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FARS2 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FARS2 protein (p.Tyr144Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early infantile epileptic encephalopathy (PMID: 22499341, 22833457, 30177229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39824). 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 FARS2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 22833457). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 15, 2012)
|
no assertion criteria provided
Method: literature only
|
COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056824.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous 431A-G transition … (more)
In 2 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous 431A-G transition in the FARS2 gene, resulting in a tyr144-to-cys (Y144C) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 114 Saudi controls. Elo et al. (2012) found that the Y144C mutation occurs in the aminoacylation domain on the interface of the anticodon stem-binding domain and may participate in stabilization of the closed structure. In vitro functional expression studies in E. coli indicated that the mutation resulted in decreased affinity for tRNA, causing a decrease in overall tRNA charging capacity. (less)
|
|
|
Likely pathogenic
(Dec 01, 2014)
|
no assertion criteria provided
(research)
Method: research
|
Global developmental delay
Mitochondrial encephalomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV000196444.1
First in ClinVar: Mar 10, 2015 Last updated: Mar 10, 2015 |
|
|
|
Pathogenic
(Jan 10, 2016)
|
no assertion criteria provided
Method: research
|
Combined oxidative phosphorylation defect type 14
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Study: The combination of WES, CNV-derived from WES, paralog studies, and GeneMatcher provide potential molecular diagnosis in a cohort from Saudi Arabia
Accession: SCV000282188.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 2
Family history: yes
|
|
|
Likely pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Combined oxidative phosphorylation defect type 14
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133175.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Combined oxidative phosphorylation defect type 14
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000891737.2
First in ClinVar: Nov 03, 2018 Last updated: Oct 01, 2022 |
Ethnicity/Population group: Arabian
|
Comment:
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FARS2 protein (p.Tyr144Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early infantile epileptic encephalopathy (PMID: 22499341, 22833457, 30177229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39824). 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 FARS2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 22833457). For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The Y144C missense variant in the FARS2 gene has been identified through whole exome sequencing in the homozygous state in three siblings with mitochondrial encephalopathy (Shamseldin et al. 2012). Functional studies found that Y144C disrupts tRNA binding and stability of the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) protein leading to a decrease in tRNA charging capacity (Elo et al. 2012). The Y144C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y144C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant to be likely pathogenic. This finding is likely consistent with a diagnosis of combined oxidative phosphorylation deficiency-14 in this patient. However, this result could also be seen if the patient had one allele with the Y144C pathogenic variant and one allele that was partially missing or refractory to amplification.
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FARS2 protein (p.Tyr144Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early infantile epileptic encephalopathy (PMID: 22499341, 22833457, 30177229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39824). 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 FARS2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 22833457). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance. | Almannai M | Molecular genetics and metabolism | 2018 | PMID: 30177229 |
| Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. | Charng WL | BMC medical genomics | 2016 | PMID: 27435318 |
| Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. | Elo JM | Human molecular genetics | 2012 | PMID: 22833457 |
| Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. | Shamseldin HE | Journal of medical genetics | 2012 | PMID: 22499341 |
Text-mined citations for rs397514610 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.