rs199476125

Positions:

• chrM-3733-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP5_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND1 missense
• Scores: Apogee2 Pathogenic 0.98
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 LHON,LHON
• Conservation: PhyloP100: 6.24

Genes affected

ND1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3733-G-A is Pathogenic according to our data. Variant chrM-3733-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9736.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND1	unassigned_transcript_4790	c.427G>A	p.Glu143Lys	missense_variant	1/1

Ensembl

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

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

LHON,LHON

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

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, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
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

Mar 24, 2022

The m.3733G>A (p.E143K) variant in MT-ND1 has been reported in 10 individuals with features of primary mitochondrial disease from 4 families. Affected individuals had features consistent with LHON and LHON-plus (PS4_moderate; PMIDs: 15505787, 27177320, 29387390). There are no reports of de novo occurrences of this variant. Segregation was only seen in one family, with healthy mother having lower heteroplasmy levels than affected child (PMID: 15505787), however this does not meet criteria for PP1_supporting (minimum 2 segregations). There are 2 occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease, and this variant is absent in gnomAD v3.1.2 and in Helix dataset (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (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_moderate, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.98
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
DEOGEN2	Uncertain	0.48	T
LIST_S2	Benign	0.85	D
MutationAssessor	Pathogenic	5.0	H
PROVEAN	Uncertain	-3.6	D
Sift4G	Uncertain	0.0040	D
GERP RS		4.5
Varity_R		0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476125; hg19: chrM-3734;