rs199474673

Variant names:

• chrM-5521-G-A
• rs199474673
• unassigned_transcript_4794:c.10G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP3 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The m.5521G>A variant in MT-TW has been reported in four unrelated individuals to date. Ages of onset included childhood (2/4 affected individuals), 20s (1/4 affected individuals), and 50s (1/4 affected individuals). Affected individuals had features including myopathy, seizures, cerebellar ataxia, mood disorders, and eating disorders. Muscle biopsies showed ragged red fibers (RRF) and COX-negative fibers, whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels of the variant were not specified in one affected individual, were 98% muscle and undetectable in blood in another affected individual, were homoplasmic in muscle and 87% brain in another affected individual, and were homoplasmic in blood in the last individual (PS4_moderate; PMIDs: 20360171, 23841600, 23847141, 9673981). There are no de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. 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 (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative RRF (89.9% +/- 11.76) than in COX-positive fibers (69.35% +/- 26.22), p<0.005 (PS3_supporting, PMID:9673981). In summary, this variant meets criteria to be classified as likely pathogenic 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 October 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254831/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNW unassigned_transcript_4794 missense
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1 Mitochondrial-myopathy
• Conservation: PhyloP100: 5.45
• Publications: 5 publications found

Genes affected

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

MT-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)

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

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

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387382.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TW	ENST00000387382.1	TSL:6	n.10G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*10G>A		downstream_gene	N/A	ENSP00000355046.4	P03891
	MT-TA	ENST00000387392.1	TSL:6	n.*66C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Mitochondrial-myopathy

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	MELAS syndrome (4)
2	-	-	Mitochondrial disease (2)
1	-	-	Inborn mitochondrial myopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	1.0
PhyloP100		5.4

Other links and lift over

dbSNP: rs199474673; hg19: chrM-5522;