M-9997-T-C

Position:

• chrM-9997-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000387429.1(MT-TG):​n.7T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-TG ENST00000387429.1 non_coding_transcript_exon
• 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

Genes affected

MT-TG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNG	TRNG.1	n.7T>C		non_coding_transcript_exon_variant	1/1
COX3	COX3.1			downstream_gene_variant			YP_003024032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TG	ENST00000387429.1	n.7T>C		non_coding_transcript_exon_variant	1/1
MT-CO3	ENST00000362079.2			downstream_gene_variant				ENSP00000354982	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0 AC: 1

Mitomap

Unspecified-patient-from-clinical-lab,MHCM

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1994

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jul 22, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434475; hg19: chrM-9998;