M-7445-A-G

Variant names:

• chrM-7445-A-G
• rs199474818
• ENST00000361624.2:c.1542A>G

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4 PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7445A>G variant is located in the MT-TS1 precursor, overlapping with MT-CO1 (Term514Term). This variant has been reported in at least 32 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PS4; PMIDs: 8019558, 8572257, 9450881, 11069477, 11175301, 15620132, 16092542, 15987292, 23525847, 18537605, 22567359, 21621438, 30035268, 26328603, 29605341, 32169613). Some individuals with this variant have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. The age of onset ranges from infancy to adulthood. The variant is primarily seen in the homoplasmic state however some individuals were reported to have low heteroplasmy levels in blood. Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There are no reports of de novo occurrences in the medical literature to our knowledge however the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. Of note, another 137 elderly individuals were found to carry this variant in platelets with heteroplasmy levels >2%, and this was reported to significantly correlate with high frequency hearing loss (PMID:26328603), however these cases were excluded from this curation given the lack of other clinical details. There is one occurrence of this variant in the Mitomap GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2. There are six heteroplasmic occurrences in the Helix dataset. Although there are several occurrences, the frequency is still low (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies supported the functional impact of this variant (PS3_supporting). One study showed a 60-70% reduction of steady state ND6 levels and 40-50% reduction of tRNASer (PMID:15694374). Other cell line studies showed significantly reduced Complex I activity, with lesser reduction in Complex IV (P=0.05; PMID 29934116). Of note, there is one early cell line study that did not demonstrate any bioenergetic impact of this variant (PMID:9247714). 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 extent of cases with similar phenotypes from different ethnic backgrounds that have been reported, that is further supported by the evidence outlined above. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120547/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 splice_region, stop_retained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1 DEAF,SNHL,SNHL
• Conservation: PhyloP100: -0.943
• Publications: 5 publications found

Genes affected

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]

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]

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

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

TRNS1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361624.2. 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-CO1	ENST00000361624.2	TSL:6	c.1542A>G	p.Ter514Ter	splice_region stop_retained	Exon 1 of 1	ENSP00000354499.2	P00395
	MT-CO2	ENST00000361739.1	TSL:6	c.-141A>G		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-TD	ENST00000387419.1	TSL:6	n.-73A>G		upstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56432

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56432

Mitomap

Disease(s): DEAF,SNHL,SNHL

Status: Reported,Cfrm-[P],Reported

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial non-syndromic sensorineural hearing loss (3)
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Palmoplantar keratoderma-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94

Other links and lift over

dbSNP: rs199474818; hg19: chrM-7446;