rs199474660

Variant names:

• chrM-3303-C-T
• rs199474660
• unassigned_transcript_4788:c.74C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 missense, splice_region
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 MMC
• Conservation: PhyloP100: 0.361

Genes affected

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3303-C-T is Pathogenic according to our data. Variant chrM-3303-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9592.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL1	unassigned_transcript_4788	c.74C>T	p.Thr25Ile	missense_variant, splice_region_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-4C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

MMC

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jul 12, 2019	The NC_012920.1:m.3303C>T variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PM7, PM9, PM10 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jan 09, 2023

The m.3303C>T variant in MT-TL1 has been reported in at least 16 unrelated individuals with primary mitochondrial disease (PS4; 13 individuals were reported in the medical literature, PMIDs: 23847141, 10431114, 32167396, 11768589, 33013660, 20226758, 23258140, 7906985, 31965079; an additional three cases were known to members of this Expert Panel). Many affected individuals had hypertrophic cardiomyopathy and/or skeletal myopathy, as well as exercise intolerance, muscle weakness, lactic acidosis, and failure to thrive. Age of onset varied from infancy to adulthood. Heteroplasmy levels in affected individuals ranged from 58-97% in muscle, 20-80% in blood, and, in one case, was almost homoplasmic in fibroblasts. There are no de novo occurrences of this variant to our knowledge. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMID: 10431114, also seen in cases known to Expert Panel members). Of note, there is a report of this variant in individuals with premature ovarian insufficiency (POI, PMID: 30404982), however this Expert Panel agreed this presentation, when isolated, is not known to be associated with mitochondrial DNA etiologies and it is not clear other organ systems were or were not screened in these cases. Therefore, these cases were not considered as supporting evidence for this variant classification. There is one occurrence in population databases as one individual in the Helix dataset had this variant present at heteroplasmy. Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (92.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing (PMID: 11271374) showed higher levels of the variant in ragged red fibers that were COX-negative (42.4±7.0%) and in ragged red fibers that were COX-positive (58.2±5.8%), and this was significantly higher than levels of the variant in normal appearing fibers (10.7±6.3%; PS3_supporting). Of note, cybrid studies are reported however the generated cybrids include other mitochondrial DNA variants precluding consideration as evidence of pathogenicity of this variant only (PMID: 30404982). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note, however, that some members of this Expert Panel elected to modify the classification to pathogenic given the extent of cases from different ethnic backgrounds that have been reported with overlapping phenotypes that is further supported by the evidence outlined above. The experts were almost evenly divided on the final classification as five experts voted to keep the classification as likely pathogenic and four voted for pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting. -

MITOCHONDRIAL CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474660; hg19: chrM-3304;