VCV000224983.24 - ClinVar

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

Germline

Classification

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.

(16)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 224983 Accession: VCV000224983.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q23.1 16: 75635982 (GRCh38) [ NCBI UCSC ] 16: 75669880 (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 9, 2016	Oct 8, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005548.3:c.599C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005539.1:p.Pro200Leu	missense
NM_001130089.2:c.683C>T	NP_001123561.1:p.Pro228Leu	missense
NM_001378148.1:c.131C>T	NP_001365077.1:p.Pro44Leu	missense
NC_000016.10:g.75635982G>A
NC_000016.9:g.75669880G>A
NG_028025.1:g.16706C>T
LRG_366:g.16706C>T
LRG_366t1:c.683C>T	LRG_366p1:p.Pro228Leu

... more HGVS ... less HGVS

Protein change

P200L, P228L, P44L

Other names

KARS1, PRO228LEU (rs201650281)

Canonical SPDI

NC_000016.10:75635981:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD) 0.00013

Exome Aggregation Consortium (ExAC) 0.00014

The Genome Aggregation Database (gnomAD), exomes 0.00014

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA358202 OMIM: 601421.0009 dbSNP: rs201650281 VarSome

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
Gene	OMIM	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.
KARS1		-	-	GRCh38 GRCh37	367	468

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.
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000210691.1
Leukoencephalopathy, progressive, infantile-onset, with or without deafness	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV002463662.4
Abnormal cerebral white matter morphology Abnormal pyramidal sign Congenital sensorineural hearing impairment Optic neuropathy Progressive cerebellar ataxia	Pathogenic (1)	no assertion criteria provided	Sep 10, 2018	RCV000681462.2
Hearing loss, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	May 1, 2024	RCV004699121.2
LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS	Pathogenic (1)	no assertion criteria provided	Mar 2, 2021	RCV001293661.2
Deafness, congenital, and adult-onset progressive leukoencephalopathy	Pathogenic (1)	no assertion criteria provided	Mar 2, 2021	RCV001293662.2
KARS1-related disorder	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 5, 2023	RCV001526444.5
Autosomal recessive nonsyndromic hearing loss 89	Likely pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000986183.1
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 29, 2023	RCV001775672.10
KARS-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 20, 2020	RCV001265601.1
Charcot-Marie-Tooth disease recessive intermediate B	Pathogenic (1)	criteria provided, single submitter	Jun 9, 2021	RCV003147413.1
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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 (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukoencephalopathy, progressive, infantile-onset, with or without deafness Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810321.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 89 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135093.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
PATHOGENIC (May 01, 2024)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: research	Hearing loss, autosomal recessive Affected status: yes Allele origin: biparental	Laboratory of Human Genetics, Universidade de São Paulo Accession: SCV005201043.2 First in ClinVar: Sep 08, 2024 Last updated: Sep 29, 2024	Comment: The KARS1:NM_001130089.2:c.683C>T variant has well-established functional studies show damaging effect on the gene or gene product (PS3), is associated with a recessive disorder, detected in … (more) The KARS1:NM_001130089.2:c.683C>T variant has well-established functional studies show damaging effect on the gene or gene product (PS3), is associated with a recessive disorder, detected in trans with a pathogenic variant, in homozygous state in affected cases (PM3), has extremely low frequency in gnomAD population databases (PM2), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Here it was found in homozygosis in two affected siblings born from unrelated couple. (less) Number of individuals with the variant: 2 Clinical Features: Hearing impairment (present) , Cerebellar ataxia (present) Family history: yes
Pathogenic (Apr 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KARS-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001443769.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: This variant has been previously reported as compound heterozygous with missense variants and frameshift variants, respectively, in children with mitochondrial respiratory chain complex deficiency features … (more) This variant has been previously reported as compound heterozygous with missense variants and frameshift variants, respectively, in children with mitochondrial respiratory chain complex deficiency features raging from hypotonia, global developmental delay, hearing loss, strabismus, ophthalmoplegia, dystonia to lactic acidosis, psychomotor retardation, spasticity and epilepsy (PMID: 23596069, 30252186, 30369941, 31116475). One ptatient's fibroblast demonstrated defective mitochondrial translation and OXPHOS biogenesis (PMID: 30252186), and biochemistry on another patient' muscle or fibroblasts showed decreased ATP production (PMID: 30369941). In addition, this alteration was shown to severely affect aminoacylation in-vitro (PMID: 31116475). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.014% (40/282774) and thus is presumed to be rare. The majority of utilized in silico tools support a deleterious effect of the c.683C>T (p.Pro228Leu) variant on protein function. Based on the available evidence, the c.683C>T (p.Pro228Leu) variant is classified as Pathogenic. (less)
Pathogenic (Apr 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KARS1-related disorder (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001736853.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: This individual was also found to have a paternally inherited heterozygous c.856_857insSVA variant in exon 7 of KARS1 (ENST00000319410). This alteration represents a mobile element … (more) This individual was also found to have a paternally inherited heterozygous c.856_857insSVA variant in exon 7 of KARS1 (ENST00000319410). This alteration represents a mobile element SINE-R/VNTR (variable number of tandem repeat)/Alu (SVA). SVAs are active non-LTR retrotransposable elements that are intermediate in size relative to Alu and L1, and are likely to be transcribed by RNA polymerase II (PMID: 22364178). (less) Number of individuals with the variant: 1 Clinical Features: Hydronephrosis (present) , Microcephaly (present) , Sensorineural hearing loss disorder (present) , Decreased response to growth hormone stimulation test (present) , Adrenal insufficiency (present) , … (more) Hydronephrosis (present) , Microcephaly (present) , Sensorineural hearing loss disorder (present) , Decreased response to growth hormone stimulation test (present) , Adrenal insufficiency (present) , Seizure (present) , Global developmental delay (present) , Generalized hypotonia (present) , Failure to thrive (present) , Growth delay (present) , Umbilical hernia (present) , Congenital laryngomalacia (present) , Left ventricular hypertrophy (present) , Gastroesophageal reflux (present) , Status epilepticus (present) , Gastrointestinal dysmotility (present) , Lactic acidosis (present) , Interictal epileptiform activity (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: Caucasians Tissue: blood
Likely pathogenic (-)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000262824.2 First in ClinVar: Apr 09, 2016 Last updated: Apr 09, 2016	Publications: PubMed (1) PubMed: 25356970 Comment: Overall WES conclusion for patient, including all identified alterations: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected Clinical Features: MR/ID/DD (present) , Brain MRI positive (present) , Phenotype is progressive (present) , Neurologic (adult onset) (present) , Oncologic (adult onset) (present) Family history: yes Sex: female Ethnicity/Population group: European-origin Geographic origin: Russia Segregation observed: yes
Pathogenic (Nov 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukoencephalopathy, progressive, infantile-onset, with or without deafness (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Centre for Inherited Metabolic Diseases, Karolinska University Hospital Accession: SCV002605387.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022
Pathogenic (Jan 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002013146.3 First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jun 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease recessive intermediate B Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835127.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Apr 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KARS1-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004013226.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PS3, PM3_Strong
Pathogenic (Mar 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023200.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002510240.3 First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 23596069‚ 30252186‚ 30369941‚ 31116475 Comment: 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). … (more) 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. (less)
Pathogenic (Dec 11, 2023)	no assertion criteria provided Method: clinical testing	KARS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004721906.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The KARS1 c.683C>T variant is predicted to result in the amino acid substitution p.Pro228Leu. This variant has been reported in the compound heterozygous state in … (more) The KARS1 c.683C>T variant is predicted to result in the amino acid substitution p.Pro228Leu. This variant has been reported in the compound heterozygous state in at least two unrelated individuals with developmental delay, hypotonia, ophthalmoplegia, sensorineural deafness and other neurologic manifestations (Lieber et al. 2013. PubMed ID: 23596069; Ruzzenente et al. 2018. PubMed ID: 30252186). This variant was also described in the compound heterozygous state in an individual who presented with severe optic neuropathy (Scheidecker et al. 2019. PubMed ID: 31116475), as well as in the homozygous state in a patient who presented with features consistent with a suspected mitochondrial disorder, including lactic acidosis and hyperechogenic liver with ascites (Felhi et al. 2020. PubMed ID: 32319008). Lastly, this variant was described in the compound heterozygous state in an individual who presented with sensorineural deafness, psychomotor retardation, spasticity, and epilepsy (Theunissen et al. 2018. PubMed ID: 30369941). Functional studies using patient fibroblasts found a multiple oxidative phosphorylation deficiency due to impaired mitochondrial translation (Ruzzenente et al. 2018. PubMed ID: 30252186). In summary, the c.683C>T variant is categorized as pathogenic for autosomal recessive KARS1-related disorders. (less)
Pathogenic (Mar 02, 2021)	no assertion criteria provided Method: literature only	LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS Affected status: not provided Allele origin: germline	OMIM Accession: SCV001482428.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Publications: PubMed (2) PubMed: 30252186‚ 31116475 Comment on evidence: Infantile-Onset Progressive Leukoencephalopathy with Deafness In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations … (more) Infantile-Onset Progressive Leukoencephalopathy with Deafness In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; 601421.0010), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism. Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; 601421.0011) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. (less)
Pathogenic (Mar 02, 2021)	no assertion criteria provided Method: literature only	DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV001482429.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Publications: PubMed (2) PubMed: 30252186‚ 31116475 Comment on evidence: Infantile-Onset Progressive Leukoencephalopathy with Deafness In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations … (more) Infantile-Onset Progressive Leukoencephalopathy with Deafness In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; 601421.0010), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism. Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; 601421.0011) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. (less)
Pathogenic (Sep 10, 2018)	no assertion criteria provided Method: research	Congenital sensorineural hearing impairment Optic neuropathy Abnormal cerebral white matter morphology Progressive cerebellar ataxia Abnormal pyramidal sign (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University Accession: SCV000808060.1 First in ClinVar: Sep 23, 2018 Last updated: Sep 23, 2018	Sex: female Geographic origin: France
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Comment:

The KARS1:NM_001130089.2:c.683C>T variant has well-established functional studies show damaging effect on the gene or gene product (PS3), is associated with a recessive disorder, detected in trans with a pathogenic variant, in homozygous state in affected cases (PM3), has extremely low frequency in gnomAD population databases (PM2), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). Here it was found in homozygosis in two affected siblings born from unrelated couple.

Comment:

This variant has been previously reported as compound heterozygous with missense variants and frameshift variants, respectively, in children with mitochondrial respiratory chain complex deficiency features raging from hypotonia, global developmental delay, hearing loss, strabismus, ophthalmoplegia, dystonia to lactic acidosis, psychomotor retardation, spasticity and epilepsy (PMID: 23596069, 30252186, 30369941, 31116475). One ptatient's fibroblast demonstrated defective mitochondrial translation and OXPHOS biogenesis (PMID: 30252186), and biochemistry on another patient' muscle or fibroblasts showed decreased ATP production (PMID: 30369941). In addition, this alteration was shown to severely affect aminoacylation in-vitro (PMID: 31116475). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.014% (40/282774) and thus is presumed to be rare. The majority of utilized in silico tools support a deleterious effect of the c.683C>T (p.Pro228Leu) variant on protein function. Based on the available evidence, the c.683C>T (p.Pro228Leu) variant is classified as Pathogenic.

Comment:

This individual was also found to have a paternally inherited heterozygous c.856_857insSVA variant in exon 7 of KARS1 (ENST00000319410). This alteration represents a mobile element SINE-R/VNTR (variable number of tandem repeat)/Alu (SVA). SVAs are active non-LTR retrotransposable elements that are intermediate in size relative to Alu and L1, and are likely to be transcribed by RNA polymerase II (PMID: 22364178).

Comment:

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)

Comment:

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.

Comment:

The KARS1 c.683C>T variant is predicted to result in the amino acid substitution p.Pro228Leu. This variant has been reported in the compound heterozygous state in at least two unrelated individuals with developmental delay, hypotonia, ophthalmoplegia, sensorineural deafness and other neurologic manifestations (Lieber et al. 2013. PubMed ID: 23596069; Ruzzenente et al. 2018. PubMed ID: 30252186). This variant was also described in the compound heterozygous state in an individual who presented with severe optic neuropathy (Scheidecker et al. 2019. PubMed ID: 31116475), as well as in the homozygous state in a patient who presented with features consistent with a suspected mitochondrial disorder, including lactic acidosis and hyperechogenic liver with ascites (Felhi et al. 2020. PubMed ID: 32319008). Lastly, this variant was described in the compound heterozygous state in an individual who presented with sensorineural deafness, psychomotor retardation, spasticity, and epilepsy (Theunissen et al. 2018. PubMed ID: 30369941). Functional studies using patient fibroblasts found a multiple oxidative phosphorylation deficiency due to impaired mitochondrial translation (Ruzzenente et al. 2018. PubMed ID: 30252186). In summary, the c.683C>T variant is categorized as pathogenic for autosomal recessive KARS1-related disorders.

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.

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Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.	Scheidecker S	Human mutation	2019	PMID: 31116475
Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause.	Theunissen TEJ	Frontiers in genetics	2018	PMID: 30369941
Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.	Ruzzenente B	Human mutation	2018	PMID: 30252186
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.	Farwell KD	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356970
Targeted exome sequencing of suspected mitochondrial disorders.	Lieber DS	Neurology	2013	PMID: 23596069

Text-mined citations for rs201650281 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201650281 ...