rs199476107

Variant names:

• chrM-14453-G-A
• rs199476107
• unassigned_transcript_4816:c.221C>T

Your query was ambiguous. Multiple possible variants found:

• chrM-14453-G-A
• chrM-14453-G-T

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 0.84
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 MELAS-/-Leigh-Disease
• Conservation: PhyloP100: 3.05

Genes affected

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)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14453-G-A is Pathogenic according to our data. Variant chrM-14453-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9692.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.221C>T	p.Ala74Val	missense_variant	Exon 1 of 1
TRNE	unassigned_transcript_4817	c.*221C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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

MELAS-/-Leigh-Disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leigh syndrome Pathogenic:1

Oct 17, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14453G>A (YP_003024037.1:p.Ala74Val) variant in MTND6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PM10, PP4, PP6, PP7 -

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.14453G>A (p.A74V) variant in MT-ND6 has been reported in at least 10 individuals with primary mitochondrial disease from 10 families. Affected individuals had onset ranging from the first day of life to adulthood (all but one case had early childhood onset, however); and with features variably consistent with Leigh syndrome and MELAS (PS4_moderate; PMIDs: 34933128, 22947169, 33644659, 32552696, 24642831, 21364701, 11781695). Heteroplasmy levels ranged from 41-83%. There are at least five reports of de novo occurrences of this variant (PM6_strong, score 2.5; PMIDs: 34933128, 33644659, 24642831, 11781695). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 2% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 0.81 (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 June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.11	D
DEOGEN2	Uncertain	0.60	D
LIST_S2	Uncertain	0.93	D
MutationAssessor	Benign	1.9	L
PROVEAN	Uncertain	-3.9	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
GERP RS		4.0
Varity_R		0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476107; hg19: chrM-14454; COSMIC: COSV62378042; COSMIC: COSV62378042;