rs199474673

Positions:

• chrM-5521-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PS3_Moderate PS4_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: MT-TW ENST00000387382.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 O:1 Mitochondrial-myopathy
• Conservation: PhyloP100: 5.45

Genes affected

MT-TW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNW (HGNC:):

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNW	TRNW.1	n.10G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TW	ENST00000387382.1	n.10G>A		non_coding_transcript_exon_variant	1/1
MT-ND2	ENST00000361453.3			downstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Mitochondrial-myopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 04, 2023	Criteria applied: PS4_MOD,PS3_SUP,PM2_SUP,PP3,PP4 -
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.5521G>A variant in MT-TW 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, PM7, PM8, PM9, PP6 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial disease Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Oct 03, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 31, 2023	The MT-TW m.5521G>A mitochondrial variant has been reported in at least five individuals with phenotypes consistent with primary mitochondrial disease including myopathy, seizures, cerebellar ataxia, mood disorders, and eating disorders (PMID: 23841600; 20360171; 9673981; 37038312; 23847141). The age of onset of disease in the affected individuals ranged between infancy and adult. In at least three of the affected individuals higher heteroplasmy levels of the variant were present in the affected tissue compared to an unaffected tissue (PMID: 9673981; 20360171; 37038312). Single fiber studies performed in muscle tissue from an adult male with progressive bilateral ptosis without ophthalmoplegia, dysphonia and mild proximal muscle wasting and weakness, showed significantly higher levels of the variant in COX-negative ragged red fibers (89.9% +/- 11.76) than in COX-positive fibers (69.35% +/- 26.22), p<0.005 (PMID: 9673981). The m.5521G>A variant is not observed in version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact tRNA structure and stability. This variant has been classified as likely pathogenic by ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel. Based on the available evidence the MT-TW m.5521G>A variant is classified as likely pathogenic for primary mitochondrial disease. -

Inborn mitochondrial myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
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: rs199474673; hg19: chrM-5522;