rs1556424691

Variant names:

• chrM-15923-A-G
• rs1556424691
• unassigned_transcript_4819:c.36A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The m.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID:1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). 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 phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM2_supporting, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA130372/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNT unassigned_transcript_4819 stop_retained
• Scores: Mitotip Uncertain 12
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 LIMM-/-MERRF-/-mito-disease
• Conservation: PhyloP100: 8.59
• Publications: 0 publications found

Genes affected

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

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]

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

TRNP Gene-Disease associations (from GenCC):

• MERRF syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNT	unassigned_transcript_4819	c.36A>G	p.Ter12Ter	stop_retained_variant	Exon 1 of 1
CYTB	unassigned_transcript_4818	c.*36A>G		downstream_gene_variant
TRNP	unassigned_transcript_4820	c.*33T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TT	ENST00000387460.2	n.36A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CYB	ENST00000361789.2	c.*36A>G		downstream_gene_variant		6		ENSP00000354554.2
MT-TP	ENST00000387461.2	n.*33T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.0440 Hom.: 792

Mitomap

Disease(s): LIMM-/-MERRF-/-mito-disease

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:2

Jun 26, 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.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). 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 phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_moderate. -

Mar 13, 2019

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Variant of unknown significance Uncertain:1

Aug 01, 1992

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Constipation;C0022346:Jaundice;C0085298:Sudden cardiac death;C1848924:Infantile onset;C1855106:Neonatal onset;C1858120:Generalized hypotonia;C2315100:Failure to thrive Uncertain:1

Sep 21, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.65
PhyloP100		8.6

Other links and lift over

dbSNP: rs1556424691; hg19: chrM-15924;