rs1057520201

Variant names:

• chrM-4132-G-A
• rs1057520201
• ENST00000361390.2:c.826G>A

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.826G>A	p.Ala276Thr	missense_variant	Exon 1 of 1
TRNI	unassigned_transcript_4790	c.-131G>A		upstream_gene_variant
TRNQ	unassigned_transcript_4791	c.*197C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.826G>A	p.Ala276Thr	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TI	ENST00000387365.1	n.-131G>A		upstream_gene_variant		6
MT-TQ	ENST00000387372.1	n.*197C>T		downstream_gene_variant		6

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

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

May 23, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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. -

not provided Uncertain:1

Jul 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.4132G>A (YP_003024026.1:p.Ala276Thr) variant in MTND1 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BP4, BP6 -

Computational scores

Source: dbNSFP v4.3

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
GERP RS		2.5
Varity_R		0.20
Mutation Taster		=59/41	polymorphism

Other links and lift over

dbSNP: rs1057520201; hg19: chrM-4133;