rs869025187

Variant names:

• chrM-14279-G-A
• rs869025187
• ENST00000361681.2:c.395C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The ENST00000361681.2(MT-ND6):​c.395C>T​(p.Ser132Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S132A) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 7)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Benign 0.060
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1 LHON
• Conservation: PhyloP100: 0.385
• 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]

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.060099654 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.395C>T	p.Ser132Leu	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.*131G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND6	ENST00000361681.2	c.395C>T	p.Ser132Leu	missense_variant	Exon 1 of 1	6		ENSP00000354665.2
MT-ND5	ENST00000361567.2	c.*131G>A		downstream_gene_variant		6		ENSP00000354813.2

Frequencies

Mitomap GenBank AF: 0.00010 AC: 7

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56417

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56417

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14279G>A (YP_003024037.1:p.Ser132Leu) 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: BS1, BP4, PP6

Leber optic atrophy Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.060
Hmtvar	Benign	0.16
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.53	T
DEOGEN2	Benign	0.18	T
LIST_S2	Benign	0.57	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.39
PROVEAN	Benign	-0.21	N
Sift	Benign	0.030	D
Sift4G	Benign	0.65	T
GERP RS		1.3
Varity_R		0.073
Mutation Taster		=100/0	polymorphism

Other links and lift over

dbSNP: rs869025187; hg19: chrM-14280; COSMIC: COSV62377821; COSMIC: COSV62377821;