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 1 ACMG points: 2P and 1B. PM2 BP7

The ENST00000000000(TRNG):​c.7T>C​(p.Leu3Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNG ENST00000000000 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 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP7: Synonymous conserved (PhyloP=1.32 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNG	unassigned_transcript_4807	c.7T>C	p.Leu3Leu	synonymous_variant	Exon 1 of 1
ND3	unassigned_transcript_4808	c.-62T>C		upstream_gene_variant
COX3	unassigned_transcript_4806	c.*7T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TG	ENST00000387429.1	n.7T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND3	ENST00000361227.2	c.-62T>C		upstream_gene_variant		6		ENSP00000355206.2
MT-CO3	ENST00000362079.2	c.*7T>C		downstream_gene_variant		6		ENSP00000354982.2

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

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Sep 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Jul 22, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Computational scores

Source: dbNSFP v4.3

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;