rs199476118

Variant names:

• chrM-3460-G-A
• rs199476118
• unassigned_transcript_4789:c.154G>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 Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND1 missense
• Scores: Apogee2 Pathogenic 0.87
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:2 LHON
• Conservation: PhyloP100: 6.38

Genes affected

ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3460-G-A is Pathogenic according to our data. Variant chrM-3460-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9722.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.154G>A	p.Ala52Thr	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*156G>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*231G>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: 0.0 AC: 0 AN: 56426

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56426

Mitomap

LHON

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:4 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant is one of the three most common causes of LHON. -

Jul 10, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 17, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3460G>A (YP_003024026.1:p.Ala52Thr) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

m.3460G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000; Howell 1992). It is estimated that 15%-25% of LHON families carry the g.3460G>A variant (Howell 1991). -

Mitochondrial disease Pathogenic:1

Apr 25, 2023

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.3460G>A (p.A52T) variant in MT-ND1 has been reported in affected individuals from more than 50 kindreds (PS4, PMIDs: 1928099, 1674640, 7629530, 1734726, 1550131, 8496715, 8024249, 8556281, 8571959, 12205655, 11906302, 12807863, 12518276, 16738010, 17122117, 18216301, 18562849, 20232220, 21887510, 25338955, 25053773, 28314831, 30053855, 30591017). While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, several individuals have been reported with multiple sclerosis. Other features have been variably seen in affected individuals including sensorineural hearing loss, auditory neuropathy, epilepsy, migraines, Parkinsonism, dystonia, Leigh syndrome, spinal cord lesions, myoclonus, myopathy, hypertension, high triglycerides, diabetes, and cardiac involvement. Testing excluding separate etiologies for these features has been limited. Heteroplasmy levels in affected individuals ranged from 58% to homoplasmy. Age of onset varied from four years old to 75 years old. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 1734726, 8571959, 11906302). There is one reported de novo occurrence to our knowledge (PM6_supporting; PMID: 12518276). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.86 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Extensive cybrid studies supported the functional impact of this variant, as do E. coli and mouse studies (PS3_moderate PMIDs: 35383288, 22079202, 15720387, 15883259, 15342361, 10976107). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM6_supporting, PP3, PS3_moderate. -

Optic atrophy Pathogenic:1

Jan 01, 2018

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MELAS syndrome Pathogenic:1

Feb 27, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v3.1.2 dataset (heteroplasmic allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 1959619). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset / ClinVar ID: VCV000009722). A different missense change at the same codon (p.Ala52Val) has been reported as pathogenic/likely pathogenic with strong evidence (Mitomap PMID: 32355048). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3 Pathogenic:1

Jul 10, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leigh syndrome 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	Pathogenic	0.87
Hmtvar	Pathogenic	0.76
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.13	D
DEOGEN2	Benign	0.13	T
LIST_S2	Benign	0.80	T
MutationAssessor	Uncertain	2.8	M
PROVEAN	Uncertain	-2.4	N
Sift4G	Pathogenic	0.0010	D
GERP RS		4.8
Varity_R		0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476118; hg19: chrM-3461; COSMIC: COSV62293268; COSMIC: COSV62293268;