chrM-4132-G-A

Variant names:

• chrM-4132-G-A
• rs1057520201
• ENST00000361390.2:c.826G>A
• MT-ND1 p.Ala276Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The m.4132G>A (p.A276T) variant in MT-ND1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on May 23, 2023. There is one family reported in the medical literature with this variant (PMID:17454741). The six affected individuals in this family had non-arteritic anterior ischemic optic neuropathy. The variant was present at homoplasmy in all affected family members and information is not provided on testing status in unaffected family members, precluding consideration for segregation evidence. There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.015%, 9/61,883; gnomAD v3.1.2: 0.019%, 11/56,428 homoplasmic occurrences; Helix: 0.041%, 80/195,893 homoplasmic occurrences). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.58 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported for this variant. 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 May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603348/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 9)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.065
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 NAION-associated
• Conservation: PhyloP100: 2.65
• Publications: 1 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)

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 1 ACMG points.

• 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.826G>A	p.Ala276Thr	missense	Exon 1 of 1	ENSP00000354687.2	P03886
	MT-TI	ENST00000387365.1	TSL:6	n.-131G>A		upstream_gene	N/A
	MT-TQ	ENST00000387372.1	TSL:6	n.*197C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.00010 AC: 9

Gnomad homoplasmic AF: 0.00019 AC: 11 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

Disease(s): NAION-associated

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.065
Hmtvar	Benign	0.12
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
DEOGEN2	Benign	0.012	T
LIST_S2	Benign	0.53	T
MutationAssessor	Benign	-1.1	N
PhyloP100		2.6
PROVEAN	Benign	-0.080	N
Sift4G	Uncertain	0.033	D
Varity_R		0.20
Mutation Taster		=59/41	polymorphism

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057520201;

hg19: chrM-4133;