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NC_012920.1(MT-TL1):m.3291T>C AND Mitochondrial disease

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 3, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV002291215.2

Allele description [Variation Report for NC_012920.1(MT-TL1):m.3291T>C]

NC_012920.1(MT-TL1):m.3291T>C

Genes:
MT-ND1:mitochondrially encoded NADH dehydrogenase 1 [Gene - OMIM - HGNC]
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.3291T>C
HGVS:
  • NC_012920.1:m.3291T>C
  • NC_012920.1:g.3291T>C
  • m.3291T>C
Links:
Genetic Testing Registry (GTR): GTR000500597; Genetic Testing Registry (GTR): GTR000556568; dbSNP: rs869312463
NCBI 1000 Genomes Browser:
rs869312463

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002583524ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(clingen mito disease acmg specifications v1-1)
Likely pathogenic
(Oct 3, 2022)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

The m.3291T>C mt-tRNA(Leu(UUR)) mutation is definitely pathogenic and causes multisystem mitochondrial disease.

Yarham JW, Blakely EL, Alston CL, Roberts ME, Ealing J, Pal P, Turnbull DM, McFarland R, Taylor RW.

J Neurol Sci. 2013 Feb 15;325(1-2):165-9. doi: 10.1016/j.jns.2012.12.003. Epub 2012 Dec 27.

PubMed [citation]
PMID:
23273904
PMCID:
PMC3560033

Details of each submission

From ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen, SCV002583524.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The m.3291T>C variant in MT-TL1 has been reported in at least eight unrelated individuals with primary mitochondrial disease. Ages of onset varied from 6- to 40-years old. Affected individuals had variable features including those consistent with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) as well as myopathy, sensorineural hearing loss, and cognitive decline. Muscle biopsies in affected individuals showed ragged red fibers (RRF), whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels ranged from 20-95% (PS4_moderate; PMIDs: 7520241, 10899447, 18977334, 20943236, 21996807, 21863273, 23273904). There are at least two de novo occurrences of this variant reported (PM6_moderate; PMIDs: 20943236, 7520241). Heteroplasmy levels tracked with disease manifestations in at least three families (PP1_moderate; PMIDs: 23273904, 21863273, 10899447). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18) than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM6_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 25, 2024