M-7465-AC-ACC

Variant names:

• chrM-7465-A-AC
• rs111033319
• unassigned_transcript_4800:c.49dupG

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4 PS3_Supporting PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID:32906214): PS4, PP1_moderate, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214937/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS1 unassigned_transcript_4800 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1 MM-/-DMDF-modulator,PEM-/-AMDF-/-Motor-neuron-disease-like
• Conservation: PhyloP100: 3.93
• Publications: 4 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 7 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387416.2. 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-TS1	ENST00000387416.2	TSL:6	n.49dupG		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-121_-120insC		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*20_*21insC		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

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

Alfa AF: 0.000337 Hom.: 3

Mitomap

Disease(s): MM-/-DMDF-modulator,PEM-/-AMDF-/-Motor-neuron-disease-like

Status: Reported,See-7471insC

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
2	-	-	Mitochondrial disease (2)
2	-	-	not provided (2)
1	-	-	Deafness, sensorineural, with neurologic features (1)
1	-	-	MERRF syndrome (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial cytochrome c oxidase deficiency (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Other links and lift over

dbSNP: rs111033319; hg19: chrM-7466;