rs201650281

Positions:

chr16-75635982-G-A

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

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

KARS1
NM_005548.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.72

Variant links:

Genes affected

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

PP5

Variant 16-75635982-G-A is Pathogenic according to our data. Variant chr16-75635982-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KARS1	NM_005548.3 linkuse as main transcript	c.599C>T	p.Pro200Leu	missense_variant	5/14	ENST00000302445.8
KARS1	NM_001130089.2 linkuse as main transcript	c.683C>T	p.Pro228Leu	missense_variant	6/15
KARS1	NM_001378148.1 linkuse as main transcript	c.131C>T	p.Pro44Leu	missense_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KARS1	ENST00000302445.8 linkuse as main transcript	c.599C>T	p.Pro200Leu	missense_variant	5/14	1	NM_005548.3	A1	Q15046-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251384

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

239

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000118

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-9.6

D;D;D;.;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.024

D;D;D;.;D

Sift4G

Uncertain

0.041

D;T;D;.;D

Polyphen

0.83

P;D;.;.;.

Vest4

0.96

MVP

0.48

MPC

0.50

ClinPred

0.99

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over