rs397515506

chrM-14568-C-T

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.106G>A(p.Gly36Ser) 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 0.83
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 LHON
• Conservation: PhyloP100: 2.34

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, 0.834105 >= 0.5 .
• PP5: Variant M-14568-C-T is Pathogenic according to our data. Variant chrM-14568-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65515.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.106G>A	p.Gly36Ser	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.

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Mitomap

LHON

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:1 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

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.14568C>T (p.G36S) variant in MT-ND6 has been reported in eight individuals from seven families, all of whom had LHON (PS4_moderate; PMIDs: 10447650, 19319978, 12324878, 22879922, 9177303). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (affected individuals: proband and brother with heteroplasmy levels ranging from 60-90%; unaffected individuals: mother and maternal aunt with lower heteroplasmy levels; PP1_moderate; PMID: 22879922). There are several occurrences in population databases, however some of these are from reported affected individuals. Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (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. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.83
Hmtvar	Pathogenic	0.73
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
DEOGEN2	Uncertain	0.53	D
LIST_S2	Uncertain	0.87	D
MutationAssessor	Benign	0.56	N
MutationTaster	Benign	1.0	D
PROVEAN	Pathogenic	-6.0	D
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.036	D
GERP RS		4.2
Varity_R		0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515506; hg19: chrM-14569;