M-9997-T-C

Variant names:

• chrM-9997-T-C
• rs121434475
• unassigned_transcript_4807:c.7T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.9997T>C variant in MT-TG has been reported in one large family to date (PMID:8079988). The most common clinical feature in affected family members was cardiomyopathy, however additional clinical features seen include renal failure, muscle cramps, muscle weakness, exercise intolerance, and gastrointestinal dysmotility. Heteroplasmy levels were variable in affected family members and appeared to segregate with cardiomyopathy but not the other clinical features (PMID:8079988). This variant is present in population databases (absent in gnomAD v3.1.2; one heteroplasmic in the Helix dataset; one homoplasmic occurrence in the Mitomap GenBank sequences; PM2_supporting). Cybrid studies support the deleterious effect of this variant (PMID:10090480; PS3_supporting). The computational predictor MitoTIP suggests this variant is deleterious (80.3 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PS3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254843/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNG unassigned_transcript_4807 synonymous
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 Unspecified-patient-from-clinical-lab,MHCM
• Conservation: PhyloP100: 1.32
• Publications: 1 publications found

Genes affected

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387429.1. 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-TG	ENST00000387429.1	TSL:6	n.7T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND3	ENST00000361227.2	TSL:6	c.-62T>C		upstream_gene	N/A	ENSP00000355206.2	P03897
	MT-CO3	ENST00000362079.2	TSL:6	c.*7T>C		downstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Unspecified-patient-from-clinical-lab,MHCM

Status: Reported,Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
-	1	-	not specified (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Benign	0.35
PhyloP100		1.3

Other links and lift over

dbSNP: rs121434475; hg19: chrM-9998;