rs397515506

Variant names:

• chrM-14568-C-T
• rs397515506
• ENST00000361681.2:c.106G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA344825/MONDO:0044970/014

• 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
• Publications: 12 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-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.106G>A	p.Gly36Ser	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-CYB	ENST00000361789.2	TSL:6	c.-179C>T		upstream_gene	N/A	ENSP00000354554.2	P00156
	MT-TE	ENST00000387459.1	TSL:6	n.*106G>A		downstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Mitomap

Disease(s): LHON

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (2)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.3
PROVEAN	Pathogenic	-6.0	D
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.036	D
GERP RS		4.2
Varity_R		0.59
Mutation Taster		=74/126	disease causing

Other links and lift over

dbSNP: rs397515506; hg19: chrM-14569;