rs587776434

Variant names:

• chrM-3890-G-A
• rs587776434
• unassigned_transcript_4789:c.584G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-3890-G-A
• chrM-3890-G-T

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: ND1 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 Progressive-Encephalomyopathy-/-Leigh-Syndrome-/-Optic-Atrophy
• Conservation: PhyloP100: 3.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3890-G-A is Pathogenic according to our data. Variant chrM-3890-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155881.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.584G>A	p.Arg195Gln	missense_variant	Exon 1 of 1

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.

Mitomap

Progressive-Encephalomyopathy-/-Leigh-Syndrome-/-Optic-Atrophy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Pathogenic:1

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.3890G>A (p.R195Q) variant in MT-ND1 has been reported in at least nine individuals from nine families in the literature, who had features falling within the Leber Hereditary Optic Neuropathy (LHON) or Leigh syndrome spectrums (PS4_moderate; PMIDs: 34390870, 33337510, 27798429, 18504678, 30095618, 23246842, 23847141). There are no reports of de novo occurrence of this variant to our knowledge. Although this variant most often is seen in the homoplasmic state, in one multi-generational family, there were five unaffected relatives with low heteroplasmy levels in urine and blood, compared to much higher levels in the proband (PP1_moderate; PMID 2324842). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease – PMID: 23246842; variant absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 23246842). 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 March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS4_moderate, PP3, PM2_supporting, PS3_supporting. -

Leigh syndrome Other:1

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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	0.93
Hmtvar	Pathogenic	0.82
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
DEOGEN2	Uncertain	0.48	T
LIST_S2	Uncertain	0.87	D
MutationAssessor	Pathogenic	5.0	H
PROVEAN	Uncertain	-3.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.82

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776434; hg19: chrM-3891;