rs397515508

chrM-3700-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000361390.2(MT-ND1):c.394G>A(p.Ala132Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.81
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 LHON
• Conservation: PhyloP100: 5.29

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: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.8132086 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND1	ENST00000361390.2	c.394G>A	p.Ala132Thr	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

LHON

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

Abnormal electroretinogram;C3665386:Visual loss;C3887709:Optic neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 21, 2016

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Mar 24, 2022

The m.3700G>A (p.A132T) variant in MT-ND1 has been reported in 3 individuals with primary mitochondrial disease who had features consistent with Leigh syndrome (1/3) and LHON (2/3; PS4_supporting; PMIDs: 30128709, 22879922, 12150954). There are no reports of de novo occurrences of this variant. There are no reports of testing in family members to date to consider for segregation. There are 3 occurrences of this variant in GenBank dataset, however 2/3 are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is present at <1/50,000 healthy individuals (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3. -

Leber optic atrophy Other:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.81
Hmtvar	Benign	0.35
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.24	T
DEOGEN2	Benign	0.18	T
LIST_S2	Benign	0.72	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	2.4e-7	A
PROVEAN	Uncertain	-3.5	D
Sift4G	Uncertain	0.0040	D
GERP RS		3.7
Varity_R		0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515508; hg19: chrM-3701;