rs199474699

Positions:

• chrM-15990-C-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: TRNP missense
• Scores: Mitotip Uncertain 13
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 MM-/-PEO
• Conservation: PhyloP100: 7.30

Genes affected

TRNP (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-15990-C-T is Pathogenic according to our data. Variant chrM-15990-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9570.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNP	unassigned_transcript_4821	c.34G>A	p.Gly12Ser	missense_variant	1/1
TRNT	unassigned_transcript_4820	c.*37C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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

MM-/-PEO

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Feb 13, 2023

The m.15990C>T variant in MT-TP gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). The age of onset ranged from the first decade of life to adulthood. Features seen in these individuals include chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance (PMIDs: 32305257, 7689388, 8190311). The variant occurred de novo in both individuals (PM6; PMIDs: 7689388, 8190311, 32305257). There are no other large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (51.7 percentile) but HmtVAR predicts it to be neutral with a score of 0.1. Single fiber testing in both reported individuals support the functional impact of this variant (PS3_supporting). In one study, there were higher levels of the variant in COX-negative fibers (91-97%) than in COX-positive fibers (63-86%, p= < 0.001; PMID: 7689388). In the other study, there were again higher levels of the variant in COX-negative fibers (89.75 ± 6.84%, n = 20) than in COX-positive fibers (14.00 ± 6.84 %, n = 17; p < 0.001; PMID: 32305257). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotype and functional testing performed in each reported individual. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PM6, PS3_supporting. -

Myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Benign	0.10

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474699; hg19: chrM-15991;