chrM-3394-T-C

Variant names:

• chrM-3394-T-C
• rs41460449
• ENST00000361390.2:c.88T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The ENST00000361390.2(MT-ND1):​c.88T>C​(p.Tyr30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y30C) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.013 (AC: 803)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.58
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2 B:1 LHON-/-Diabetes-/-CPTdeficiency-/-high-altitude-adaptation
• Conservation: PhyloP100: 3.15
• Publications: 64 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 -7 ACMG points.

• PP3: Apogee2 supports a deletorius effect, 0.5821793 >= 0.5 .
• BA1: High frequency in mitomap database: 0.013099999

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.88T>C	p.Tyr30His	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*90T>C		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*165T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.88T>C	p.Tyr30His	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*90T>C		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*165T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.013 AC: 803

Gnomad homoplasmic AF: 0.0091 AC: 514 AN: 56420

Gnomad heteroplasmic AF: 0.00021 AC: 12 AN: 56420

Alfa AF: 0.0109 Hom.: 539

Mitomap

Disease(s): LHON-/-Diabetes-/-CPTdeficiency-/-high-altitude-adaptation

Status: Reported-[VUS]--population-dependent|-hg-M9-marker

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

May 12, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The m.3394T>C variant is found at a frequency of 1.3% in MITOMAP (identified in 409 out of 32,059 sequences). When this variant has been reported in Leber hereditary optic neuropathy (LHON) patients, it is typically found alongside a primary variant; normally m.14484T>C (Brown 1995). The exact contribution of secondary variants such as m.3394T>C to the LHON phenotype is not fully understood, although data indicate that m.3394T>C likely influences the LHON phenotype in an ethnic-specific manner. While the frequency of m.3394T>C in Japanese LHON patients was not increased over controls (Matsumoto 1999), this mutation was found in 8.5% of Caucasian LHON patients compared to 1.1% of controls (Brown 1995). Furthermore, m.3394T>C was identified in four Chinese families effected with a low penetrance form of LHON (Liang 2009). m.3394T>C was identified in these families in the absence of any primary variant, suggesting that it plays a critical role in the LHON phenotype, either in isolation or by modifying other as-yet unidentified factors. -

Leber optic atrophy Pathogenic:1

Nov 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Sep 11, 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.3394T>C (p.Y30H) variant in MT-ND1 has been reported in 157 individuals with phenotypes consistent with primary mitochondrial disease, including Leber Hereditary Optic Neuropathy (LHON) and diabetes. This variant was present in 2.1% of 1,741 individuals in one cohort of LHON, and is thought to increase penetrance and occurrence of optic neuropathy in families when present with the well-known pathogenic variant, m.11778G>A (PMID: 30597069). The m.3394T>C variant is widely considered a secondary "helper" variant, not a variant associated with primary mitochondrial disease. However, of the 157 cases reported to date, the m.3394T>C variant has been reported without an accompanying primary mitochondrial disease-associated variant in 31 LHON families, two individuals with diabetes, and one individual with hypertrophic cardiomyopathy (PS4). Although outside the scope of this curation, this variant also been shown to be adaptive for high-altitude Tibetans where multiple independent origins of m.3394T>C have been documented (PMID: 22517755). The variant is present in 100% in Tibetan-associated haplogroups M9a (349/349) and M9b (4/4) in MITOMAP. In a study of type 2 diabetes mellitus in Han Chinese, this variant was found with significantly higher frequency in affected individuals (23.6%) than in the controls (2.0%; PMID: 18679013). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.76 (Min=0, Max=1; APOGEE2 score is 0.582), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that this variant can either be deleterious or beneficial depending on haplogroup and environmental context. The variant reduces both complex I activity and NADH-linked respiration especially when on non-M9 haplogroups. In Asia, this variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, this variant is enriched on the M9 background in Tibet. When present on the M9 background, this variant is associated with a complex I activity that is equal to or higher than that of the wild type sequence on other haplotype backgrounds (B4c and F1; PMID: 22517755). In a cybrid study of East Asian metabolic syndrome (PMID: 29997041), complex I activity of the cells with this variant had lower complex I activity than cells with the wild type sequence, and that these lower complex I levels correlated with increased risk for metabolic phenotypes. Addition of this variant further reduced the complex I activity on cybrids of B4c, F1, and M9 haplogroup backgrounds (PS3_supporting). 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 September 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PS3_supporting, PS4. -

Optic atrophy Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

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.3394T>C (YP_003024026.1:p.Tyr30His) 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.58
Hmtvar	Benign	0.34
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.37	T
DEOGEN2	Benign	0.14	T
LIST_S2	Benign	0.68	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.1
PROVEAN	Pathogenic	-4.4	D
Sift4G	Uncertain	0.040	D
GERP RS		3.6
Varity_R		0.68
Mutation Taster		=63/37	polymorphism

Other links and lift over

dbSNP: rs41460449; hg19: chrM-3395;