chr16-75635982-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_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:17

Conservation

PhyloP100: 9.72

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 89
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
leukoencephalopathy, progressive, infantile-onset, with or without deafness
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease recessive intermediate B
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

KARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 224983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3 link	c.599C>T	p.Pro200Leu	missense_variant	Exon 5 of 14	ENST00000302445.8	NP_005539.1	Q15046-1
KARS1	NM_001130089.2 link	c.683C>T	p.Pro228Leu	missense_variant	Exon 6 of 15		NP_001123561.1	Q15046-2
KARS1	NM_001378148.1 link	c.131C>T	p.Pro44Leu	missense_variant	Exon 5 of 14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8 link	c.599C>T	p.Pro200Leu	missense_variant	Exon 5 of 14	1	NM_005548.3	ENSP00000303043.3		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

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251384

AF XY:

0.000140

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 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

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000184

AC:

205

AN:

1111946

Other (OTH)

AF:

0.0000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000188

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:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KARS1: PM3:Very Strong, PM2, PS3:Supporting -

Mar 19, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 11, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

KARS1-related disorder

Pathogenic:3

Apr 05, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM3_Strong -

Dec 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Apr 20, 2020

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Leukoencephalopathy, progressive, infantile-onset, with or without deafness

Pathogenic:2

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2022

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormal pyramidal sign;C0393525:Progressive cerebellar ataxia;C0948163:Abnormal cerebral white matter morphology;C1865866:Congenital sensorineural hearing impairment;C3887709:Optic neuropathy

Pathogenic:1

Sep 10, 2018

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Pathogenic:1

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 09, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deafness, congenital, and adult-onset progressive leukoencephalopathy

Pathogenic:1

Mar 02, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

KARS-related disorder

Pathogenic:1

Apr 20, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hearing loss, autosomal recessive

Pathogenic:1

May 01, 2024

Laboratory of Human Genetics, Universidade de São Paulo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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. -

LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS

Pathogenic:1

Mar 02, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Autosomal recessive nonsyndromic hearing loss 89

Pathogenic:1

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;T;.;T;.

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

MutationAssessor

Uncertain

2.8

.;M;.;.;.

PhyloP100

9.7

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

PromoterAI

-0.051

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.85

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over