rs1603218588

Variant names:

• chrM-1630-A-G
• rs1603218588
• unassigned_transcript_4786:c.29A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3_Supporting PP3 PP4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The m.1630A>G variant in MT-TV has been reported in two unrelated individuals. One individual had features consistent with mitochondrial neurogastrointestinal encephalopathy (MNGIE) with additional features of hearing loss, mild psychomotor delay, headache, and small stature (PMID:19252805). Another individual had features consistent with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in addition to bilateral sensorineural hearing loss, myopia, short stature requiring growth hormone supplementation, and delayed onset of puberty (PMID:21540128; PS4_supporting). The variant was heteroplasmic in the individual with MNGIE-like features at 90% in muscle and 70% in blood, with 60% heteroplasmy being seen in the asymptomatic mother’s blood (PMID:19252805). In the individual with MELAS, the variant was present at 75% heteroplasmy in blood, 95% in urine, and 90% in fibroblasts; the variant was present in the mother at 93% in blood, 98% in urine, and 95% in fibroblasts (PMIDs: 21540128, 30709774). No correlating segregations or de novo occurrences of this variant were found in our review of the literature. The computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). The m.1630A>G variant is absent in the GenBank dataset, the Helix dataset (although there are four heteroplasmic occurrences), and gnomAD3.1.2 (PM2_supporting). Single-fiber testing (PMID:19252805) showed 90% heteroplasmy in COX-negative fibers and 50% in COX-positive fibers. Cybrids showed marked decrease in cytochrome-c oxidase activity. Oxygen consumption/respiration activity was also greatly reduced in both homoplasmic and heteroplasmic cybrid lines. Northern blotting showed a pronounced loss of MTTV in mutant cybrids when compared to controls (PMID:21540128; PS3_supporting). Electron transport enzyme activities were assessed in one of the individuals and her healthy mother, and showed a significant difference between the proband and the mother and a healthy control individual. Exome sequencing was performed in the proband and her mother, ruling out other known genetic etiologies (PMID:30709774; PP4). 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 November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PP3, PM2_supporting, PS3_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913163293/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNV unassigned_transcript_4786 missense
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 MNGIE-like-disease-/-MELAS
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

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 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387342.1. 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-TV	ENST00000387342.1	TSL:6	n.29A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR2	ENST00000387347.2	TSL:6	n.-41A>G		upstream_gene	N/A
	MT-RNR1	ENST00000389680.2	TSL:6	n.*29A>G		downstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): MNGIE-like-disease-/-MELAS

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	MELAS syndrome (2)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	1.0
PhyloP100		1.9

Other links and lift over

dbSNP: rs1603218588; hg19: chrM-1632;