rs587776438

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND3	unassigned_transcript_4808	c.196G>A	p.Asp66Asn	missense_variant	Exon 1 of 1
ND4L	unassigned_transcript_4810	c.-216G>A		upstream_gene_variant
TRNR	unassigned_transcript_4809	c.-151G>A		upstream_gene_variant
TRNG	unassigned_transcript_4807	c.*196G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.196G>A	p.Asp66Asn	missense_variant	Exon 1 of 1	6		ENSP00000355206.2
MT-ND4L	ENST00000361335.1	c.-216G>A		upstream_gene_variant		6		ENSP00000354728.1
MT-TR	ENST00000387439.1	n.-151G>A		upstream_gene_variant		6
MT-TG	ENST00000387429.1	n.*196G>A		downstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): Leigh-Disease

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Oct 23, 2023

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.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. -

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	0.92
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;