rs869025186

chrM-14498-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM1 PM2 PP3

The ENST00000361681.2(MT-ND6):c.176A>G(p.Tyr59Cys) 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 Uncertain significance (★). 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 0.96
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1 LHON
• Conservation: PhyloP100: 3.10

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript ENST00000361681.2 (MT-ND6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical (size 20) in uniprot entity NU6M_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000361681.2
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.96350706 >= 0.5 .

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.176A>G	p.Tyr59Cys	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

LHON

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Uncertain significance, 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.14498T>C (YP_003024037.1:p.Tyr59Cys) variant in MTND6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BP4, PP6 -

Leber optic atrophy Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.96
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.061	T
DEOGEN2	Pathogenic	0.85	D
LIST_S2	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PROVEAN	Pathogenic	-8.8	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.0
Varity_R		0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869025186; hg19: chrM-14499;