M-5703-G-A

Position:

• chrM-5703-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNN synonymous
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Pathogenic reviewed by expert panel P:3 CPEO-/-MM
• Conservation: PhyloP100: 1.61

Genes affected

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

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

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-5703-G-A is Pathogenic according to our data. Variant chrM-5703-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9620.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNN	unassigned_transcript_4796	c.27C>T	p.Cys9Cys	synonymous_variant	1/1
TRNA	unassigned_transcript_4795	c.-48C>T		upstream_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

CPEO-/-MM

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Ophthalmoplegia, isolated Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Feb 13, 2023

The m.5703G>A variant in MT-TN has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate). These four individuals were from three different backgrounds including African American (one individual), Chinese (one individual), and Caucasian (two individuals, one from France and one from Spain). Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), as well as exercise intolerance, severe underweight, and hearing loss (PMIDs: 8254046, 14518831, 30897601, 32419253). The variant in these four cases was seen at varying degrees of heteroplasmy in muscle (14-80%), blood (5-48%), urine (4-11%), and buccal (7-59%). The variant was reported to have arisen de novo in three of the four affected individuals (PM6_strong, PMIDs: 8254046, 30897601, 32419253) and no details about family member testing were provided for the other individual. Furthermore, the variant’s presence in individuals of different ethnic backgrounds was also considered as indirect evidence of a de novo occurrence at some time in the past. There are no other large families reported in the medical literature to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP predicts this variant to be pathogenic, scoring in the 89.9 percentile and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). Multiple independent studies support the functional impact of this variant (PS3_supporting). Single-fiber testing in two of the four affected individuals was performed and showed that the variant was present at higher heteroplasmy in COX-negative fibers than COX-positive fibers (93% heteroplasmy in COX-negative fibers compared to 2% in COX-positive fibers in one individual, P<.0001, PMID: 32419253; and 97-100% in COX-negative fibers compared to 3-63% in COX-positive fibers in the other individual, PMID: 8254046). Furthermore, cybrids with high levels of the variant demonstrated a severe mitochondrial protein synthesis defect and impaired oxidative phosphorylation (PMIDs: 8254046, 9372914). tRNA conformational studies showed impaired aminoacylation with severe reduction of the tRNA Asn pool (PMID: 9372914). In summary, this variant meets criteria to be classified as likely pathogenic however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given consistent functional evidence of severe deleterious effect across multiple independent studies and given repeated apparent de novo occurrences across individuals of different ethnic backgrounds. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_supporting, PP3, PM2_supporting, PM6_strong. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476130; hg19: chrM-5704;