rs1603218931

Variant names:

• chrM-3391-G-A
• rs1603218931
• ENST00000361390.2:c.85G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361390.2(MT-ND1):​c.85G>A​(p.Gly29Ser) variant causes a missense change. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.00090 (AC: 54)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Uncertain 0.41
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 LHON
• Conservation: PhyloP100: 6.25
• Publications: 0 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]

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.405958 < 0.5 .
• BP6: Variant M-3391-G-A is Benign according to our data. Variant chrM-3391-G-A is described in ClinVar as [Benign]. Clinvar id is 692348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 19

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.85G>A	p.Gly29Ser	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*87G>A		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*162G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.85G>A	p.Gly29Ser	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*87G>A		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*162G>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.00090 AC: 54

Gnomad homoplasmic AF: 0.00034 AC: 19 AN: 56425

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56425

Alfa AF: 0.000445 Hom.: 2

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3391G>A (YP_003024026.1:p.Gly29Ser) variant in MTND1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.41
Hmtvar	Pathogenic	0.87
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.15	T
DEOGEN2	Benign	0.13	T
LIST_S2	Benign	0.80	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PROVEAN	Pathogenic	-4.9	D
Sift4G	Benign	0.10	T
GERP RS		4.5
Varity_R		0.86
Mutation Taster		=38/62	disease causing

Other links and lift over

dbSNP: rs1603218931; hg19: chrM-3392;