rs201650281
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_005548.3(KARS1):c.599C>T(p.Pro200Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P200P) has been classified as Likely benign.
Frequency
Consequence
NM_005548.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KARS1 | NM_005548.3 | c.599C>T | p.Pro200Leu | missense_variant | 5/14 | ENST00000302445.8 | |
KARS1 | NM_001130089.2 | c.683C>T | p.Pro228Leu | missense_variant | 6/15 | ||
KARS1 | NM_001378148.1 | c.131C>T | p.Pro44Leu | missense_variant | 5/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KARS1 | ENST00000302445.8 | c.599C>T | p.Pro200Leu | missense_variant | 5/14 | 1 | NM_005548.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251384Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135892
GnomAD4 exome AF: 0.000163 AC: 239AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126AN XY: 727216
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74324
ClinVar
Submissions by phenotype
KARS1-related disorder Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 05, 2023 | PS3, PM3_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Apr 20, 2020 | 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). - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 19, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | 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. - |
Leukoencephalopathy, progressive, infantile-onset, with or without deafness Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Nov 22, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Abnormal pyramidal sign;C0393525:Progressive cerebellar ataxia;C0948163:Abnormal cerebral white matter morphology;C1865866:Congenital sensorineural hearing impairment;C3887709:Optic neuropathy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Sep 10, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | - | Overall WES conclusion for patient, including all identified alterations: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected - |
Charcot-Marie-Tooth disease recessive intermediate B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 09, 2021 | - - |
Deafness, congenital, and adult-onset progressive leukoencephalopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 2021 | - - |
KARS-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Apr 20, 2020 | 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. - |
LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 2021 | - - |
Autosomal recessive nonsyndromic hearing loss 89 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at