rs199476143

Positions:

• chrM-1606-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNV missense
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 AMDF
• Conservation: PhyloP100: -0.0990

Genes affected

TRNV (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-1606-G-A is Pathogenic according to our data. Variant chrM-1606-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9548.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNV	unassigned_transcript_4787	c.5G>A	p.Ser2Asn	missense_variant	1/1
RNR1	unassigned_transcript_4786	n.*5G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

AMDF

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia, progressive seizures, mental deterioration, and hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

MELAS syndrome Pathogenic:1

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.1606G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jun 30, 2022

The m.1606G>A variant in MT-TV has been reported in two affected individuals in two families (PMIDs: 9450773, 2056939), however haplogroups were not provided as necessary to apply PS4_supporting. These two individuals had strikingly similar courses, as both were males who were relatively healthy until their 20s/30s when they developed progressive cognitive impairment. Other features seen in both men include bilateral cataracts, bilateral SNHL, imbalance/ataxia, and basal ganglia classifications, with both men harboring the variant at 67-70% heteroplasmy. This variant occurred de novo in one individual (absent in blood and urine from mother and brother; PM6_supporting, PMID: 12056939). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at <10% in muscle, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (85%) than in COX positive fibers (57%), p<0.0001 (PS3_supporting, PMID: 9450773). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 73.6%, as does HmtVar with a score of 0.9 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476143; hg19: chrM-1608; COSMIC: COSV63763043;