rs199476119

Variant names:

• chrM-4160-T-C
• rs199476119
• ENST00000361390.2:c.854T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM6_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4160T>C (p.L285P) variant in MT-ND1 has been reported in three unrelated individuals to date (PMIDs: 2018041, 22258525, 35699829), however only one case was included in this curation (PMID:35699829). This individual had Leber Hereditary Optic Neuropathy (LHON) and dystonia, and the variant was present at 80.2% in blood, 90.8% in urine, and 81.7% in buccal. This variant occurred de novo in this individual as it was absent in blood, buccal, and urine samples from his mother and sister (PM6_supporting, PMID:35699829). One of the other reported families with this variant had LHON however they also had the m.14484T>C variant, one of the three most common variants associated with LHON (PMIDs: 2018041, 29249004), and therefore was not included in this curation. Another individual was reported to have developmental delay, vision involvement, peripheral nervous system involvement, and muscle involvement however the m.4160T>C variant was only present at 11% heteroplasmy (PMID:22258525). Given the low heteroplasmy, this case was also excluded from this curation. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.89 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are single occurrences in population databases, however these are from reported affected individuals (PM2_supporting). Cybrid studies were performed however were not considered in this curation given the presence of other mitochondrial DNA variants (PMIDs: 35699829, 28455970). In summary, this variant meets criteria to be classified as uncertain significance 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 January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3, PM6_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340942/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 LHON-/-LHON-plus
• Conservation: PhyloP100: 7.63
• Publications: 32 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]

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

TRNQ Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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: 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.854T>C	p.Leu285Pro	missense	Exon 1 of 1	ENSP00000354687.2	P03886
	MT-TI	ENST00000387365.1	TSL:6	n.-103T>C		upstream_gene	N/A
	MT-TM	ENST00000387377.1	TSL:6	n.-242T>C		upstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56420

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56420

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): LHON-/-LHON-plus

Status: Reported---possibly-synergistic

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.88
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
DEOGEN2	Benign	0.36	T
LIST_S2	Benign	0.75	T
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.6
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.97

Other links and lift over

dbSNP: rs199476119; hg19: chrM-4161;