rs387906421

chrM-14674-T-CchrM-14674-T-G

Variant summary

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

The ENST00000387459.1(MT-TE):n.69A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TE ENST00000387459.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 9.6
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy
• Conservation: PhyloP100: -1.00

Genes affected

MT-TE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE (HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14674-T-C is Pathogenic according to our data. Variant chrM-14674-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9618.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNE	TRNE.1	n.69A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TE	ENST00000387459.1	n.69A>G		non_coding_transcript_exon_variant	1/1
MT-ND6	ENST00000361681.2			upstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56429

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56429

Mitomap

Reversible-COX-deficiency-myopathy,Reversible-COX-deficiency-myopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jan 23, 2023	The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial myopathy with reversible cytochrome C oxidase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2011

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 26, 2014

- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Jul 12, 2019

The NC_012920.1:m.14674T>C variant in MT-TE gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PP4, PP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.6
Hmtvar	Pathogenic	0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906421; hg19: chrM-14675;