rs397515506

Variant names:

• chrM-14568-C-T
• rs397515506
• unassigned_transcript_4816:c.106G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND6 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

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]

CYTB (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)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• 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 rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.106G>A	p.Gly36Ser	missense_variant	Exon 1 of 1
CYTB	unassigned_transcript_4818	c.-179C>T		upstream_gene_variant
TRNE	unassigned_transcript_4817	c.*106G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

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

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -

Mitochondrial disease Pathogenic:1

Jun 30, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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
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;