rs397515507

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrM-3635-G-A
• chrM-3635-G-T

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:4 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. 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-ND1	ENST00000361390.2	TSL:6	c.329G>A	p.Ser110Asn	missense	Exon 1 of 1	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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Leber optic atrophy (3)
1	-	-	Leber optic atrophy and dystonia (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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;