Variant M-3243-A-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

No frequency data in Mitomap. Probably very rare.

PP5

Variant M-3243-A-T is Pathogenic according to our data. Variant chrM-3243-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689856.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons
TRNL1	unassigned_transcript_4789 use as main transcript	c.14A>T	p.Glu5Val	missense_variant	1/1
RNR2	unassigned_transcript_4788 use as main transcript	n.*14A>T		downstream_gene_variant
	use as main transcript

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome

Cov.:

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

Mitomap

MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

MELAS syndrome

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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.3243A>T variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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: PS3, PS5, PM5, PP3 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Pathogenic and reported on 08-31-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mitochondrial disease

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Oct 10, 2022

The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), as well as myoclonic epilepsy, exercise intolerance with rhabdomyolysis, cataracts, sensorineural hearing loss, diabetes, peripheral neuropathy, and ataxia (PMIDs: 9168904, 18203188, 20471262, 23220830, 30210801, 33924034, 25504047; PS4_moderate). In all individuals, the variant was present at heteroplasmy, ranging from 69-99% in muscle and 13-50% in blood. Age of onset varied from six to 29 years old. There are no large families reported in the medical literature to consider for evidence of segregation. There are no de novo occurrences of this variant reported to our knowledge. The m.3243A>T variant is absent in the GenBank dataset and gnomAD3.1.2. There is one heteroplasmic occurrence in 195,893 sequences in the Helix database, however the overall frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 58.8 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.8 (PP3). The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with likely pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PM5_supporting, PS3_moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mitotip

Uncertain

Hmtvar

Pathogenic

0.80

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

M-3243-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation