rs118203885

Positions:

• chrM-583-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PS4_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The m.583G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease. The first was a woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) who also had retinal dystrophy, ataxia, and dystonic posturing (PMID:9771776). The second reported individual had myopathy and retinal dystrophy (PMID 16806928). The variant in the first case was heteroplasmic in the patient’s muscle (58%) but undetectable blood. The variant was also undetectable in the mother's blood. In the second case, the variant was heteroplasmic (79%) in the patient’s muscle but undetectable in other tissues. The ages of onset in the two cases were 12 and 17 years, respectively (PS4_supporting). There are no large families reported in the medical literature to consider for evidence of segregation. The variant was reported de novo in one case report as it was absent in mother’s blood (PMID:9771776), however the variant was also absent in the proband’s blood, no additional tissues were tested, and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. There are no other reports of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 93.1 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). The m.583G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD3.1.2 (PM2_supporting). A single-fiber study (PMID:16806928) showed the variant heteroplasmy to be higher in COX-negative fibers (78±22%; n = 11) than in COX-positive fibers (45±16%; n = 15; P < 0.001). An aminoacylation study (PMID:17878308) showed significant losses in aminoacylation efficiency for this variant (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PS3_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254834/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TF ENST00000387314.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 MELAS-/-MM-&-EXIT
• Conservation: PhyloP100: 8.61

Genes affected

MT-TF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

TRNF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNF	TRNF.1	n.7G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TF	ENST00000387314.1	n.7G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

MELAS-/-MM-&-EXIT

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -
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.583G>A variant in MT-TF 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, PM7, PM8, PP4, PP6 -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Oct 10, 2022

The m.583G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease. The first was a woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) who also had retinal dystrophy, ataxia, and dystonic posturing (PMID: 9771776). The second reported individual had myopathy and retinal dystrophy (PMID 16806928). The variant in the first case was heteroplasmic in the patient’s muscle (58%) but undetectable blood. The variant was also undetectable in the mother's blood. In the second case, the variant was heteroplasmic (79%) in the patient’s muscle but undetectable in other tissues. The ages of onset in the two cases were 12 and 17 years, respectively (PS4_supporting). There are no large families reported in the medical literature to consider for evidence of segregation. The variant was reported de novo in one case report as it was absent in mother’s blood (PMID: 9771776), however the variant was also absent in the proband’s blood, no additional tissues were tested, and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. There are no other reports of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 93.1 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). The m.583G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD3.1.2 (PM2_supporting). A single-fiber study (PMID: 16806928) showed the variant heteroplasmy to be higher in COX-negative fibers (78±22%; n = 11) than in COX-positive fibers (45±16%; n = 15; P < 0.001). An aminoacylation study (PMID: 17878308) showed significant losses in aminoacylation efficiency for this variant (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS3_supporting, PP3, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
Hmtvar	Pathogenic	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203885; hg19: chrM-585;