NM_005548.3(KARS1):c.599C>T (p.Pro200Leu) AND KARS1-related disorder

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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 11, 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:: RCV001526444.4

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]

Observations:

Condition(s)

Name:: KARS1-related disorder
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001736853	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013226	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004721906	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001736853

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 20, 2020)

maternal

clinical testing

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

SCV004013226

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 5, 2023)

germline

clinical testing

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

SCV004721906

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 11, 2023)

germline

clinical testing

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

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
Caucasians	maternal	yes	1	1	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

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV001736853.1

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

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	blood	not provided		1	not provided	1	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004013226.1

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

Description

PS3, PM3_Strong

#	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 PreventionGenetics, part of Exact Sciences, SCV004721906.1

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

Description

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.

#	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 29, 2024

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