rs199476119

Positions:

• chrM-4160-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3 PM2_Supporting PM6_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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.854T>C	p.Leu285Pro	missense_variant	1/1			ENSP00000354687	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56420

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56420

Mitomap

LHON-/-LHON-plus

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1991	- -
not provided, no classification provided	literature only	GeneReviews	-	This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jan 08, 2024

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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.0000067	A
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476119; hg19: chrM-4161;