rs199474701

Variant names:

• chrM-15967-G-A
• rs199474701
• unassigned_transcript_4820:c.57C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID:19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy. This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID:19273760). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (78.9 percentile) and HmtVAR predicts it to be deleterious with a score of 0.65 (PP3). It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%. Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID:19273760). 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PP3, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120550/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNP unassigned_transcript_4820 synonymous
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 MERRF-like-disease
• Conservation: PhyloP100: -1.86
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387461.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TP	ENST00000387461.2	TSL:6	n.57C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-CYB	ENST00000361789.2	TSL:6	c.*80G>A		downstream_gene	N/A	ENSP00000354554.2	P00156
	MT-TT	ENST00000387460.2	TSL:6	n.*14G>A		downstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MERRF-like-disease

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (1)
1	-	-	MERFF syndrome (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.65
PhyloP100		-1.9

Other links and lift over

dbSNP: rs199474701; hg19: chrM-15968;