M-14482-C-G

Position:

• chrM-14482-C-G

Variant summary

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

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

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

Genes affected

ND6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14482-C-G is Pathogenic according to our data. Variant chrM-14482-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65513.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND6	unassigned_transcript_4817	c.192G>C	p.Met64Ile	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

LHON,LHON

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jul 11, 2022

The m.14482C>G (p.M64I) variant in MT-ND6 has been reported in one proband from an extended consanguineous kindred with primary mitochondrial disease. The predominant feature in this family was bilateral optic atrophy consistent with Leber Hereditary Optic Neuropathy (LHON). The variant was present at homoplasmy in affected and unaffected individuals from this family and, when affected, the age of onset was early adulthood (PMID: 9443868). It appears some individuals from this family were reported multiple times (PMIDs: 21887510, 8742999). There are no reported de novo occurrences of this variant to our knowledge. The variant was homoplasmic in family members of the only reported proband, precluding consideration for segregation evidence. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this nucleotide position leading to the same amino acid change was classified as likely pathogenic by this expert panel, m.14482C>A (p.M64I, PS1). Furthermore, a different 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). 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). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt uncertain significance was a more appropriate classification given the only reported family was consanguineous and nuclear genetic etiologies were not assessed. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS1, PM5, PP3. -

Leber optic atrophy Other:1

not provided, no classification provided

literature only

GeneReviews

-

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

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	-0.26	T
DEOGEN2	Benign	0.33	T
LIST_S2	Benign	0.73	T
MutationAssessor	Uncertain	2.1	M
PROVEAN	Benign	-1.3	N
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
GERP RS		-0.73
Varity_R		0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476108; hg19: chrM-14483;