rs199474699

Variant names:

• chrM-15990-C-T
• rs199474699
• unassigned_transcript_4820:c.34G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM6 PS3_Supporting PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120549/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNP unassigned_transcript_4820 missense
• Scores: Mitotip Uncertain 13
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 MM-/-PEO
• Conservation: PhyloP100: 7.30
• Publications: 2 publications found

Genes affected

TRNP (HGNC:7494): (mitochondrially encoded tRNA proline)

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNT (HGNC:7499): (mitochondrially encoded tRNA threonine)

TRNT Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNP	unassigned_transcript_4820	c.34G>A	p.Gly12Ser	missense_variant	Exon 1 of 1
CYTB	unassigned_transcript_4818	c.*103C>T		downstream_gene_variant
TRNT	unassigned_transcript_4819	c.*37C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TP	ENST00000387461.2	n.34G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CYB	ENST00000361789.2	c.*103C>T		downstream_gene_variant		6		ENSP00000354554.2
MT-TT	ENST00000387460.2	n.*37C>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MM-/-PEO

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Feb 13, 2023

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jul 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Benign	0.10
PhyloP100		7.3

Other links and lift over

dbSNP: rs199474699; hg19: chrM-15991;