NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 11, 2022
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:: RCV000200808.18

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_033003.2:g.356835C>T
NM_001318872.2:c.1082C>T
NM_001374875.1:c.1082C>T
NM_001374876.1:c.1082C>T
NM_001374877.1:c.1082C>T
NM_001374878.1:c.1082C>T
NM_001374879.1:c.1082C>T
NM_001375257.1:c.1082C>T
NM_001375258.1:c.950C>T
NM_001375259.1:c.386C>T
NM_001375260.1:c.386C>T
NM_006567.5:c.1082C>TMANE SELECT
NP_001305801.1:p.Pro361Leu
NP_001361804.1:p.Pro361Leu
NP_001361805.1:p.Pro361Leu
NP_001361806.1:p.Pro361Leu
NP_001361807.1:p.Pro361Leu
NP_001361808.1:p.Pro361Leu
NP_001362186.1:p.Pro361Leu
NP_001362187.1:p.Pro317Leu
NP_001362188.1:p.Pro129Leu
NP_001362189.1:p.Pro129Leu
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:

P129L; PRO361LEU

Links:

OMIM: 611592.0008; dbSNP: rs751459058

NCBI 1000 Genomes Browser:

rs751459058

Molecular consequence:

NM_001318872.2:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374875.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374876.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374877.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374878.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374879.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375257.1:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375258.1:c.950C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375259.1:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375260.1:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006567.5:c.1082C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251375	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 11, 2022)	germline	clinical testing	Citation Link,
SCV002064423	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251375

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 11, 2022)

germline

clinical testing

Citation Link,

SCV002064423

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 5, 2020)

germline

clinical testing

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

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

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

Details of each submission

From GeneDx, SCV000251375.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30250868, 28043061, 26553276, 32989326, 29126765, 30177229, 21234346, 31683770, 32007496, 34426522)

#	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 Genetic Services Laboratory, University of Chicago, SCV002064423.1

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

Description

The sequence change, c.1082C>T, in exon 6 results in an amino acid change, p.Pro361Leu. The p.Pro361Leu change affects a highly conserved amino acid residue located in an anticodon binding domain of the FARS2 protein that is known to be functional. The p.Pro361Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This particular amino acid change has been described in the compound heterozygous state in two unrelated patients with FARS2 deficiency with spastic paraplegia phenotype (PMID: 29126765). Functional studies using the fibroblasts from these individuals showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes (PMID: 29126765). This sequence change has been described in the gnomAD database with an overall low population frequency of 0.013%(dbSNP rs751459058).

#	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

Last Updated: Apr 20, 2024

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