chrM-7510-T-C

Position:

• chrM-7510-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS1 missense
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 SNHL
• Conservation: PhyloP100: 1.24

Genes affected

TRNS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-7510-T-C is Pathogenic according to our data. Variant chrM-7510-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9565.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNS1	unassigned_transcript_4801	c.5A>G	p.Lys2Arg	missense_variant	1/1
TRND	unassigned_transcript_4802	c.-8T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

SNHL

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Mar 13, 2023

The m.7510T>C variant in MT-TS1 has been reported in at least nine individuals across six different families with primary mitochondrial disease (PS4_moderate; PMIDs: 29299381, 18028453, 23430555, 15292920, 10978361, 12471220). The most common feature in affected individuals was sensorineural hearing loss. Age of onset ranged from 2-70 years old, and heteroplasmy levels in affected individuals ranged from 90% to >99%. Of note, some unaffected family members had the variant present at homoplasmy, as well (PMID: 12471220). Additional clinical features were seen in at least two families. One family reported in the medical literature also had migraines, ataxia, short stature, epilepsy, cognitive impairment, tremor, and restless leg syndrome (PMID: 29299381). The second family was known to some members of this expert panel, and the expert panel agreed to include this case. This variant segregated with disease manifestations in two families with hearing loss as all affected individuals had the variant present at heteroplasmy levels ranging from 90% to >99% (PP1_moderate; PMIDs: 29299381, 10978361). There are no de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474820; hg19: chrM-7511;