M-14596-A-T

Variant names:

• chrM-14596-A-T
• rs387906424
• ENST00000361681.2:c.78T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.14596A>T (p.I26M) variant in MT-ND6 has been reported in one family with primary mitochondrial disease to date (PMID:8644732). Affected individuals had clinical features consistent with Leber Hereditary Optic Neuropathy (LHON) and/or spastic dystonia. Of note, another variant was seen in this family (m. 11696G>A), however this is present in healthy population databases and likely haplogroup-associated. The m.14596A>T variant was present at homoplasmy in affected individuals. As all tested individuals were homoplasmic for the variant, segregation evidence could not be considered. There are no additional families reported with de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computation predictor APOGEE predicts this variant to be deleterious (score 0.95 in APOGEE1 and 0.86 in APOGEE2; PP3). 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 August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120626/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.86
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 LHON-with-hereditary-spastic-dystonia
• Conservation: PhyloP100: 0.690
• Publications: 13 publications found

Genes affected

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]

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

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.78T>A	p.Ile26Met	missense	Exon 1 of 1	ENSP00000354665.2
	MT-CYB	ENST00000361789.2	TSL:6	c.-151A>T		upstream_gene	N/A	ENSP00000354554.2
	MT-TE	ENST00000387459.1	TSL:6	n.*78T>A		downstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): LHON-with-hereditary-spastic-dystonia

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy and dystonia Pathogenic:1

Apr 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

Aug 14, 2023

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.14596A>T (p.I26M) variant in MT-ND6 has been reported in one family with primary mitochondrial disease to date (PMID: 8644732). Affected individuals had clinical features consistent with Leber Hereditary Optic Neuropathy (LHON) and/or spastic dystonia. Of note, another variant was seen in this family (m. 11696G>A), however this is present in healthy population databases and likely haplogroup-associated. The m.14596A>T variant was present at homoplasmy in affected individuals. As all tested individuals were homoplasmic for the variant, segregation evidence could not be considered. There are no additional families reported with de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computation predictor APOGEE predicts this variant to be deleterious (score 0.95 in APOGEE1 and 0.86 in APOGEE2; PP3). 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 August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3.

Leber optic atrophy Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.86
Hmtvar	Pathogenic	0.75
AlphaMissense	Uncertain	0.39
PhyloP100		0.69
Mutation Taster		=47/53	disease causing

Other links and lift over

dbSNP: rs387906424; hg19: chrM-14597;