rs199476107

chrM-14453-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PP3 PP5_Very_Strong

The ENST00000361681.2(MT-ND6):c.221C>T(p.Ala74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript ENST00000361681.2 (MT-ND6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.8418123 >= 0.5 .
• 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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND6	ENST00000361681.2	c.221C>T	p.Ala74Val	missense_variant	1/1			P1

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

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

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. -

Leigh syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

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 -

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
MutationTaster	Benign	1.0	D
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;