M-7445-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP7

The ENST00000361624.2(MT-CO1):c.1542A>G(p.Ter514=) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

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

Genes affected

COX1 (HGNC:):

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-TS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-7445-A-G is Pathogenic according to our data. Variant chrM-7445-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9563.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.943 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX1	COX1.1	c.1542A>G	p.Ter514=	stop_retained_variant	1/1
TRNS1	TRNS1.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO1	ENST00000361624.2	c.1542A>G	p.Ter514=	stop_retained_variant	1/1			P1
MT-TS1	ENST00000387416.2			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56432

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56432

Mitomap

DEAF,SNHL,SNHL

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Palmoplantar keratoderma-deafness syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Aug 08, 2022

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. -

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

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.7445A>G variant in MT-TS1 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, PS5 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199474818; hg19: chrM-7446;