rs199476108

Variant names:

• chrM-14482-C-A
• rs199476108
• ENST00000361681.2:c.192G>T

Your query was ambiguous. Multiple possible variants found:

• chrM-14482-C-A
• chrM-14482-C-G
• chrM-14482-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.14482C>A (p.M64I) variant in MT-ND6 has been reported in at least five unrelated individuals with LHON (PS4_moderate; PMIDs: 19319978, 12112086, 11931086, 12150954). Ages of onset varied from 10-29-years-old. All affected individuals had the variant present at homoplasmy. There are no reports of de novo occurrences to our knowledge. Several extended families have been reported in the medical literature (PMIDs: 11931086, 12112086) however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for PP1. There are two occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant – m.14484T>C (p.M64V, PM5). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM2_supporting, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340934/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.97
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 LHON,LHON
• Conservation: PhyloP100: -3.83
• Publications: 15 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]

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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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 rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.192G>T	p.Met64Ile	missense_variant	Exon 1 of 1
TRNE	unassigned_transcript_4817	c.*192G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND6	ENST00000361681.2	c.192G>T	p.Met64Ile	missense_variant	Exon 1 of 1	6		ENSP00000354665.2
MT-TE	ENST00000387459.1	n.*192G>T		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.000377 Hom.: 7

Mitomap

Disease(s): LHON,LHON

Status: Cfrm-[LP],Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -

Mitochondrial disease Pathogenic:1

Jun 30, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.14482C>A (p.M64I) variant in MT-ND6 has been reported in at least five unrelated individuals with LHON (PS4_moderate; PMIDs: 19319978, 12112086, 11931086, 12150954). Ages of onset varied from 10-29-years-old. All affected individuals had the variant present at homoplasmy. There are no reports of de novo occurrences to our knowledge. Several extended families have been reported in the medical literature (PMIDs: 11931086, 12112086) however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for PP1. There are two occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant – m.14484T>C (p.M64V, PM5). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PM5, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.97
Hmtvar	Pathogenic	0.79
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.20	T
DEOGEN2	Benign	0.33	T
LIST_S2	Benign	0.73	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-3.8
PROVEAN	Benign	-1.3	N
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
GERP RS		-0.73
Varity_R		0.47

Other links and lift over

dbSNP: rs199476108; hg19: chrM-14483;