ENST00000361390.2:c.329G>A

Variant names:

• chrM-3635-G-A
• rs397515507
• ENST00000361390.2:c.329G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4 PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3635G>A (p.S110N) variant in MT-ND1 has been reported in >16 individuals with primary mitochondrial disease, and more specifically Leber's hereditary optic neuropathy (LHON). This variant has been observed in affected individuals primarily in the homoplasmic state to date (20/21 cases) (PS4; PMIDs: 25194554, 21074518, 23304069,19527690, 19497304, 11479733, 33417421). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in Helix and the GenBank dataset. It is present in gnomAD 3.1 in 1/56428 individuals (0.002%). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 25194554, 11479733). 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 August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PS3_supporting, PP3, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA344827/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 LHON
• Conservation: PhyloP100: 6.35
• Publications: 43 publications found

Genes affected

MT-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]

MT-ND1 Gene-Disease associations (from GenCC):

• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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
ND1	unassigned_transcript_4789	c.329G>A	p.Ser110Asn	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.329G>A	p.Ser110Asn	missense_variant	Exon 1 of 1	6		ENSP00000354687.2

Frequencies

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

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56428

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56428

Alfa AF: 0.0000854 Hom.: 1

Mitomap

Disease(s): LHON

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:2 Other:1

Oct 17, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3635G>A (YP_003024026.1:p.Ser110Asn) variant in MTND1 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM10, PP4 -

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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. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Aug 23, 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.3635G>A (p.S110N) variant in MT-ND1 has been reported in >16 individuals with primary mitochondrial disease, and more specifically Leber's hereditary optic neuropathy (LHON). This variant has been observed in affected individuals primarily in the homoplasmic state to date (20/21 cases) (PS4; PMIDs: 25194554, 21074518, 23304069,19527690, 19497304, 11479733, 33417421). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in Helix and the GenBank dataset. It is present in gnomAD 3.1 in 1/56428 individuals (0.002%). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 25194554, 11479733). 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 August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PP3, PS4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.80
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.022	T
DEOGEN2	Uncertain	0.44	T
LIST_S2	Benign	0.73	T
MutationAssessor	Pathogenic	4.8	H
PhyloP100		6.4
PROVEAN	Uncertain	-2.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.83
Mutation Taster		=39/161	disease causing

Other links and lift over

dbSNP: rs397515507; hg19: chrM-3636;