NM_005548.3(KARS1):c.599C>T (p.Pro200Leu) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 29, 2023
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:: RCV001775672.9

Allele description

NM_005548.3(KARS1):c.599C>T (p.Pro200Leu)

Gene:

KARS1:lysyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q23.1

Genomic location:

Preferred name:

NM_005548.3(KARS1):c.599C>T (p.Pro200Leu)

Other names:

KARS1, PRO228LEU (rs201650281)

HGVS:

NC_000016.10:g.75635982G>A
NG_028025.1:g.16706C>T
NM_001130089.2:c.683C>T
NM_001378148.1:c.131C>T
NM_005548.3:c.599C>TMANE SELECT
NP_001123561.1:p.Pro228Leu
NP_001123561.1:p.Pro228Leu
NP_001365077.1:p.Pro44Leu
NP_005539.1:p.Pro200Leu
NP_005539.1:p.Pro200Leu
LRG_366t1:c.683C>T
LRG_366:g.16706C>T
LRG_366p1:p.Pro228Leu
NC_000016.9:g.75669880G>A
NM_001130089.1:c.683C>T
NM_005548.2:c.599C>T
p.Pro228Leu

Protein change:

P200L; PRO228LEU

Links:

OMIM: 601421.0009; dbSNP: rs201650281

NCBI 1000 Genomes Browser:

rs201650281

Molecular consequence:

NM_001130089.2:c.683C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378148.1:c.131C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005548.3:c.599C>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
SCV002013146	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 11, 2022)	germline	clinical testing	Citation Link,
SCV002023200	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002510240	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 29, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23596069, 30252186, 30369941, 31116475, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002013146

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 11, 2022)

germline

clinical testing

Citation Link,

SCV002023200

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 19, 2021)

germline

clinical testing

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

SCV002510240

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 29, 2023)

germline

clinical testing

PubMed (5)
[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 exome sequencing of suspected mitochondrial disorders.

Lieber DS, Calvo SE, Shanahan K, Slate NG, Liu S, Hershman SG, Gold NB, Chapman BA, Thorburn DR, Berry GT, Schmahmann JD, Borowsky ML, Mueller DM, Sims KB, Mootha VK.

Neurology. 2013 May 7;80(19):1762-70. doi: 10.1212/WNL.0b013e3182918c40. Epub 2013 Apr 17.

PubMed [citation]

PMID:: 23596069
PMCID:: PMC3719425

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV002013146.3

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

Description

Published in vitro functional studies demonstrate a strongly decreased aminoacylation activity compared with wild type KARS, which may result in decreased level of translation of the nuclear encoded lysine rich proteins belonging to the respiratory chain complex (Scheidecker et al., 2019); Associated with multiple oxidative phosphorylation deficiency in patient fibroblasts and the mitochondrial translation is specifically inhibited in patient fibroblasts expressing this mutant protein (Ruzzenente et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25356970, 23596069, 30252186, 29875423, 29615062, 30709774, 30369941, 31116475, 34172899, 32319008, 33972171)

#	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 Revvity Omics, Revvity, SCV002023200.3

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

#	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

From Invitae, SCV002510240.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 228 of the KARS protein (p.Pro228Leu). This variant is present in population databases (rs201650281, gnomAD 0.1%). This missense change has been observed in individuals with nonsyndromic deafness with mitochondrial features (PMID: 23596069, 30252186, 30369941, 31116475). ClinVar contains an entry for this variant (Variation ID: 224983). 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 not expected to disrupt KARS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KARS function (PMID: 31116475). 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: Sep 16, 2024

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