rs41460449

chrM-3394-T-C

Variant summary

Our verdict is Benign. Variant got -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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1 LHON-/-Diabetes-/-CPTdeficiency-/-high-altitude-adaptation
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND1	ENST00000361390.2	c.88T>C	p.Tyr30His	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

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: 0.0120 Hom.: 517

Mitomap

LHON-/-Diabetes-/-CPTdeficiency-/-high-altitude-adaptation

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 12, 2017

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1992

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

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
MutationTaster	Benign	0.000087	A
PROVEAN	Pathogenic	-4.4	D
Sift4G	Uncertain	0.040	D
GERP RS		3.6
Varity_R		0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41460449; hg19: chrM-3395;