rs28616230

Variant names:

• chrM-4171-C-A
• rs28616230
• ENST00000361390.2:c.865C>A

Your query was ambiguous. Multiple possible variants found:

• chrM-4171-C-A
• chrM-4171-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID:12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are no reports of de novo occurrences to our knowledge. Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID:12112111) however this did not meet criteria to be considered for PP1. This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID:19616643). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. In the future, once three or more unrelated cases are reported, criteria for a likely pathogenic classification would be met. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022 (PMID:32906214): Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340948/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.80
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 O:1 LHON-/-Leigh-like-phenotype
• Conservation: PhyloP100: -0.734
• Publications: 26 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 4 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND1	ENST00000361390.2	TSL:6	c.865C>A	p.Leu289Met	missense	Exon 1 of 1	ENSP00000354687.2
	MT-TI	ENST00000387365.1	TSL:6	n.-92C>A		upstream_gene	N/A
	MT-TM	ENST00000387377.1	TSL:6	n.-231C>A		upstream_gene	N/A

Frequencies

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

Mitomap

Disease(s): LHON-/-Leigh-like-phenotype

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Leber optic atrophy (4)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.80
Hmtvar	Pathogenic	0.68
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.044	T
DEOGEN2	Benign	0.017	T
LIST_S2	Uncertain	0.91	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.73
PROVEAN	Benign	0.050	N
GERP RS		-0.51
Varity_R		0.62
Mutation Taster		=88/12	polymorphism

Other links and lift over

dbSNP: rs28616230; hg19: chrM-4172;