rs121434458

Variant names:

• chrM-5591-G-A
• rs121434458
• unassigned_transcript_4795:c.65C>T

Your query was ambiguous. Multiple possible variants found:

• chrM-5591-G-A
• chrM-5591-G-T

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: 𝑓 0.0 (AC: 0)
• Consequence: TRNA missense
• Scores: Mitotip Uncertain 15
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 Myopathy
• Conservation: PhyloP100: 2.27

Genes affected

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-5591-G-A is Pathogenic according to our data. Variant chrM-5591-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9625.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNA	unassigned_transcript_4795	c.65C>T	p.Ser22Phe	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.*80G>A		downstream_gene_variant
TRNN	unassigned_transcript_4796	c.*66C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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 GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56420

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56420

Mitomap

Myopathy

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1 Uncertain:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 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.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID: 16476954). There are no reported de novo occurrences of this variant to our knowledge. 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 pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID: 16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting. -

MELAS syndrome Pathogenic:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.5591G>A variant in MT-TA 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, PM8, PM9, PP3, PP6 -

Inborn mitochondrial myopathy Pathogenic:1

Feb 14, 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	15
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: rs121434458; hg19: chrM-5592;