rs199476130

chrM-5703-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387400.1(MT-TN):n.27C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TN ENST00000387400.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Pathogenic reviewed by expert panel P:3 CPEO-/-MM
• Conservation: PhyloP100: 1.61

Genes affected

MT-TN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNN (HGNC:):

MT-TA (HGNC:7475): (mitochondrially encoded tRNA alanine)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• 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	UniProt
TRNN	TRNN.1	n.27C>T		non_coding_transcript_exon_variant	1/1
TRNA	TRNA.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TN	ENST00000387400.1	n.27C>T		non_coding_transcript_exon_variant	1/1
MT-TA	ENST00000387392.1			upstream_gene_variant

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;