M-14674-T-G

Variant names:

• chrM-14674-T-G
• rs387906421
• unassigned_transcript_4817:c.69A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.14674T>G variant in MT-TE has been reported in two affected individuals with reversible infantile respiratory chain deficiency from a Japanese cohort (PMID:21194154). One girl presented with congenital myopathy and muscle weakness, and muscle biopsy at age 8 months showed ragged red fibers. Blood and cerebrospinal fluid (CSF) lactate levels were normal. By age 15 years, she had no persistent medical concerns. The variant was present at homoplasmy in muscle. The other reported individual, also a girl, presented with mitochondrial myopathy and failure to thrive. Muscle biopsy at age 5 months showed ragged red fibers and reduced respiratory chain enzyme activities. She had elevated blood creatine kinase and lactate, and elevated CSF lactate. By age 11 years, she had mild exercise intolerance only. The variant was present at homoplasmy in muscle. There was no mention of testing in family members of either proband. There are no reported de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are inconsistent for this variant as MitoTIP suggests this variant is benign (29.4 percentile) and HmtVAR predicts it to be deleterious (0.4). Another variant at this position was classified as likely pathogenic by this Expert Panel (m.14674T>C, PM5_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 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 March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA128830/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNE unassigned_transcript_4817 missense, splice_region
• Scores: Mitotip Uncertain 9.6
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy
• Conservation: PhyloP100: -1.00
• Publications: 1 publications found

Genes affected

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• Leber plus disease

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387459.1. 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-TE	ENST00000387459.1	TSL:6	n.69A>C		splice_region non_coding_transcript_exon	Exon 1 of 1
	MT-CYB	ENST00000361789.2	TSL:6	c.-73T>G		upstream_gene	N/A	ENSP00000354554.2	P00156
	MT-ND6	ENST00000361681.2	TSL:6	c.-1A>C		upstream_gene	N/A	ENSP00000354665.2	P03923

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
1	-	-	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.6
Hmtvar	Pathogenic	0.40
PhyloP100		-1.0

Other links and lift over

dbSNP: rs387906421; hg19: chrM-14675;