rs118203887

Variant names:

• chrM-622-G-A
• rs118203887
• unassigned_transcript_4784:c.46G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The m.622G>A variant in MT-TF has been reported in one individual to date, in a woman with adult-onset myopathy and neuropathy. She was healthy until her early 60s when she developed exercise intolerance, fatigue, paresthesia, muscle cramps, and mild hearing impairment. Muscle biopsy showed several atrophic fibers, COX-deficient fibers, subsarcolemmal mitochondrial accumulation, and enlarged mitochondria with paracrystalline inclusions. She had reductions in complex I (50% controls), complex III (68% controls), and complex IV (55% controls) activities. The variant was present at 88% heteroplasmy in muscle, 70% in hair, 66% in urine, 63% in buccal sample, and 36% in blood (PMID:16769874). Her mother was reported to have similar walking difficulties but did not undergo testing for this variant. Her healthy daughter had the variant present at lower heteroplasmy levels however her daughter was younger than the proband was at symptom onset. This variant is present in population databases (absent in Mitomap's GenBank sequences; one heteroplasmic and one homoplasmic occurrence in gnomAD v3.1.2; eight heteroplasmic occurrences in the Helix dataset). Single fiber testing showed higher levels of the variant in COX-negative fibers (93%±1.0; N = 11) than in COX-positive fibers (82%±8.5; N = 14), p<0.001 (PS3_supporting, PMID:16769874). Aminoacylation defects and tRNA structural changes were also reported (PMID:17878308). The computational predictor MitoTIP suggests this variant is neutral (41.5 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7. 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 June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120551/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNF unassigned_transcript_4784 missense
• Scores: Mitotip Uncertain 12
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 EXIT-&-Deafness
• Conservation: PhyloP100: 5.21
• Publications: 2 publications found

Genes affected

TRNF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNF	unassigned_transcript_4784	c.46G>A	p.Asp16Asn	missense_variant	Exon 1 of 1
RNR1	unassigned_transcript_4785	n.-26G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TF	ENST00000387314.1	n.46G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-RNR1	ENST00000389680.2	n.-26G>A		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56417

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56417

Alfa AF: 0.0000272 Hom.: 0

Mitomap

Disease(s): EXIT-&-Deafness

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1 Uncertain:1

Jun 24, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.622G>A variant in MT-TF has been reported in one individual to date, in a woman with adult-onset myopathy and neuropathy. She was healthy until her early 60s when she developed exercise intolerance, fatigue, paresthesia, muscle cramps, and mild hearing impairment. Muscle biopsy showed several atrophic fibers, COX-deficient fibers, subsarcolemmal mitochondrial accumulation, and enlarged mitochondria with paracrystalline inclusions. She had reductions in complex I (50% controls), complex III (68% controls), and complex IV (55% controls) activities. The variant was present at 88% heteroplasmy in muscle, 70% in hair, 66% in urine, 63% in buccal sample, and 36% in blood (PMID: 16769874). Her mother was reported to have similar walking difficulties but did not undergo testing for this variant. Her healthy daughter had the variant present at lower heteroplasmy levels however her daughter was younger than the proband was at symptom onset. This variant is present in population databases (absent in Mitomap's GenBank sequences; one heteroplasmic and one homoplasmic occurrence in gnomAD v3.1.2; eight heteroplasmic occurrences in the Helix dataset). Single fiber testing showed higher levels of the variant in COX-negative fibers (93%±1.0; N = 11) than in COX-positive fibers (82%±8.5; N = 14), p<0.001 (PS3_supporting, PMID: 16769874). Aminoacylation defects and tRNA structural changes were also reported (PMID: 17878308). The computational predictor MitoTIP suggests this variant is neutral (41.5 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7. 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 June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, mitochondrial, late-onset Pathogenic:1

Jun 01, 2006

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	12
Hmtvar	Pathogenic	0.70
PhyloP100		5.2

Other links and lift over

dbSNP: rs118203887; hg19: chrM-624;