NC_012920.1(MT-TL1):m.3243A>G AND Mitochondrial disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 14, 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:: RCV000495738.4

Allele description [Variation Report for NC_012920.1(MT-TL1):m.3243A>G]

NC_012920.1(MT-TL1):m.3243A>G

Gene:

MT-TL1:mitochondrially encoded tRNA leucine 1 (UUA/G) [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Genomic location:

Preferred name:

NC_012920.1(MT-TL1):m.3243A>G

Other names:

A3243G; MT-TL1 m.3243A>G

HGVS:

NC_012920.1:m.3243A>G
NC_012920.1:g.3243A>G
m.3243A>G

Nucleotide change:

3243A-G

Links:

Genetic Testing Registry (GTR): GTR000556568; OMIM: 590050.0001; dbSNP: rs199474657

NCBI 1000 Genomes Browser:

rs199474657

Observations:

Condition(s)

Name:: Mitochondrial disease
Synonyms:: Mitochondrial diseases; Mitochondrial disorder
Identifiers:: MONDO: MONDO:0044970; MeSH: D028361; MedGen: C0751651; Orphanet: 68380

Recent activity

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low-density lipoprotein receptor isoform 1 precursor [Homo sapiens]
low-density lipoprotein receptor isoform 1 precursor [Homo sapiens]
gi|4504975|ref|NP_000518.1|

Protein
transforming protein RhoA [Bos taurus]
transforming protein RhoA [Bos taurus]
gi|28603756|ref|NP_788818.1|

Protein
Micromonas virus MicBV39 DNA polymerase gene, partial cds
Micromonas virus MicBV39 DNA polymerase gene, partial cds
gi|565341063|gb|KF378578.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000577894	Wellcome Centre for Mitochondrial Research, Newcastle University	no assertion criteria provided	Pathogenic (May 22, 2017)	germline	clinical testing
SCV000599945	Donald Williams Parsons Laboratory, Baylor College of Medicine - CSER-BASIC3 See additional submitters Donald Williams Parsons Laboratory, Baylor College of Medicine	no assertion criteria provided	Pathogenic (Jul 31, 2013)	somatic	research	PubMed (3) [See all records that cite these PMIDs] 11085913, 15372523, 26822237
SCV004101341	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Aug 14, 2023)	unknown	clinical testing	Citation Link,
SCV005044159	New York Genome Center - PrenatalSEQ	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Nov 2, 2022)	inherited	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	40	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Hispanic Americans	somatic	unknown	1	1	not provided	not provided	not provided	research

Citations

PubMed

Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study.

Rahman S, Poulton J, Marchington D, Suomalainen A.

Am J Hum Genet. 2001 Jan;68(1):238-40. Epub 2000 Nov 20.

PubMed [citation]

PMID:: 11085913
PMCID:: PMC1234919

Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis.

Shanske S, Pancrudo J, Kaufmann P, Engelstad K, Jhung S, Lu J, Naini A, DiMauro S, De Vivo DC.

Am J Med Genet A. 2004 Oct 1;130A(2):134-7.

PubMed [citation]

PMID:: 15372523

See all PubMed Citations (3)

Details of each submission

From Wellcome Centre for Mitochondrial Research, Newcastle University, SCV000577894.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	40	not provided	not provided	clinical testing	not provided

#	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		40	not provided	not provided	not provided

From Donald Williams Parsons Laboratory, Baylor College of Medicine - CSER-BASIC3, SCV000599945.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Hispanic Americans	1	not provided	not provided	research (GTR000508680.4)	PubMed (3)

Description

This variant has been previously reported as disease-causing. It was an incidental finding in our study, in a 5-year-old female with choroid plexiform carcinoma. There was 23% heteroplasmy detected in blood.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	unknown	not provided	Blood	not provided	(GTR000508680.4)	1	not provided	1	not provided

From Illumina Laboratory Services, Illumina, SCV004101341.1

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

Description

The MT-TL1 m.3243A>G mitochondrial variant has been reported in the literature in a heteroplasmic state in at least 16 individuals with primary mitochondrial disease and is found in approximately 80% of individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (PMID: 2102678; 2268345; 1715668; 1732728; 27296531; 20301411). The level of heteroplasmy of this variant shows a significant correlation with the clinical signs and symptoms observed in patients and the severity of the clinical presentation (PMID: 27296531). The variant has been identified in a confirmed de novo state in at least four individuals with primary mitochondrial disease (PMID: 27331024; 11168879; 8926502). Cybrid studies support the functional impact of this variant (PMID: 1732728). Multiple lines of computational evidence suggest the variant may have a deleterious effect on gene function. Based on the available evidence, the m.3243A>G variant is classified as pathogenic for primary mitochondrial disease.

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

From New York Genome Center - PrenatalSEQ, SCV005044159.1

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

Description

The heteroplasmic m.3243A>G variant was detected in 77% of reads in the fetal specimen (amniotic fluid), and detected in 15.8% of reads in the maternal specimen. The m.3243A>G variant is one of the most common pathogenic variants reported in the mitochondrial genome and has been identified in ~80% individuals with MELAS [PMID:20301411], and has also been reported in indiviudals with MIDD, MERRF, and other syndromic and non-syndromic mitochondrial phenotypes (for Review [PMID:36276941]). It is reported in ClinVar as Pathogenic/Likely Pathogenic (VarID:9589) with 29 submissions and no conflicts. The m.3243A>G variant is within the D-loop domain of the mitochondrial tRNA for Leucine (MT-TL1) [PMID: 2102678] and leads to faulty tRNA processing and enzyme maturation (for Review, [PMID:36276941]). The heteroplasmic m.3243A>G variant identified is reported here as Pathogenic.

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

Last Updated: Oct 26, 2024

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