M-14709-T-C

Position:

• chrM-14709-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PS4 PP1_Moderate PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.14709T>C variant in MT-TE has been reported in at least 39 affected individuals from 20 kindreds (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15048886, 15880407, 15607216, 17161635, 17891417, 20045353, 26469001, 26885883, 29941710, 32313153, 33304817, 32948797; web story: https://www.chop.edu/stories/mitochondrial-disease-noras-story; PS4). Age of onset ranged from shortly after birth to 50s, although there are some reports of decreased fetal movements and hydrops fetalis. Features in affected individuals include myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, hearing loss, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Furthermore, this variant has been reported in some individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap and myoclonic epilepsy with ragged red fibers (MERRF). Muscle biopsies in affected individuals showed ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities. The variant was present at variable levels in affected and unaffected individuals. Some healthy family members had the variant present at homoplasmy, however heteroplasmy levels were generally higher in more severely affected individuals. The variant was present at 78% to homoplasmy in muscle and was variable among tissues from the same individual. There are no reported de novo occurrences to our knowledge. The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate). The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID:7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; 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, PP1_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120580/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TE ENST00000387459.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 13
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 MM+DMDF-/-Encephalomyopathy-/-Dementia+diabetes+ophthalmoplegia
• Conservation: PhyloP100: 0.942

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNE	TRNE.1	n.34A>G		non_coding_transcript_exon_variant	1/1
CYTB	CYTB.1			upstream_gene_variant			YP_003024038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TE	ENST00000387459.1	n.34A>G		non_coding_transcript_exon_variant	1/1
MT-ND6	ENST00000361681.2			upstream_gene_variant				ENSP00000354665	P1
MT-CYB	ENST00000361789.2			upstream_gene_variant				ENSP00000354554	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

MM+DMDF-/-Encephalomyopathy-/-Dementia+diabetes+ophthalmoplegia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:2

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.14709T>C variant in MT-TE has been reported in at least 39 affected individuals from 20 kindreds (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15048886, 15880407, 15607216, 17161635, 17891417, 20045353, 26469001, 26885883, 29941710, 32313153, 33304817, 32948797; web story: https://www.chop.edu/stories/mitochondrial-disease-noras-story; PS4). Age of onset ranged from shortly after birth to 50s, although there are some reports of decreased fetal movements and hydrops fetalis. Features in affected individuals include myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, hearing loss, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Furthermore, this variant has been reported in some individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap and myoclonic epilepsy with ragged red fibers (MERRF). Muscle biopsies in affected individuals showed ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities. The variant was present at variable levels in affected and unaffected individuals. Some healthy family members had the variant present at homoplasmy, however heteroplasmy levels were generally higher in more severely affected individuals. The variant was present at 78% to homoplasmy in muscle and was variable among tissues from the same individual. There are no reported de novo occurrences to our knowledge. The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate). The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; 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, PP1_moderate, PM2_supporting, PP3, PS3_supporting. -

Myopathy, mitochondrial, with diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

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.14709T>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, PP3, PP4, PP6 -

Diabetes-deafness syndrome maternally transmitted Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

Inborn mitochondrial myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434453; hg19: chrM-14710;