chrM-10254-G-A

Variant names:

• chrM-10254-G-A
• rs587776438
• ENST00000361227.2:c.196G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM6 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.10254G>A (p.D66N) variant in MT-ND3 has been reported in at least five unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with Leigh syndrome, with onset in or around the first year of life, and two individuals had features of optic neuropathy (PS4_moderate; PMIDs: 20202874, 27290639, 26238931, 36913248). There are at least two de novo occurrences reported in the literature (PM6; PMIDs: 20202874, 27290639). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.56 and 0.925, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM6, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345916/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Pathogenic 0.92
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1 Leigh-Disease
• Conservation: PhyloP100: 7.79
• Publications: 7 publications found

Genes affected

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE 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.
• PM6: 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: ENST00000361227.2. 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-ND3	ENST00000361227.2	TSL:6	c.196G>A	p.Asp66Asn	missense	Exon 1 of 1	ENSP00000355206.2	P03897
	MT-ND4L	ENST00000361335.1	TSL:6	c.-216G>A		upstream_gene	N/A	ENSP00000354728.1	P03901
	MT-TR	ENST00000387439.1	TSL:6	n.-151G>A		upstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): Leigh-Disease

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.92
Hmtvar	Pathogenic	0.81
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.088	D
DEOGEN2	Pathogenic	0.84	D
LIST_S2	Uncertain	0.95	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PROVEAN	Pathogenic	-4.8	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
GERP RS		5.1
Varity_R		0.78

Other links and lift over

dbSNP: rs587776438; hg19: chrM-10255;