M-1630-A-G

Position:

• chrM-1630-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3 PP4 PS3_Supporting 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: MT-TV ENST00000387342.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 MNGIE-like-disease-/-MELAS
• Conservation: PhyloP100: 1.94

Genes affected

MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

TRNV (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNV	TRNV.1	n.29A>G		non_coding_transcript_exon_variant	1/1
RNR2	RNR2.1			upstream_gene_variant
RNR1	RNR1.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TV	ENST00000387342.1	n.29A>G		non_coding_transcript_exon_variant	1/1
MT-RNR2	ENST00000387347.2			upstream_gene_variant
MT-RNR1	ENST00000389680.2			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

MNGIE-like-disease-/-MELAS

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jul 12, 2019	The NC_012920.1:m.1630A>G variant in MT-TV gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PP4, PP6 -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Nov 14, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1603218588; hg19: chrM-1632;