ENST00000361567.2:c.1177G>C

Variant names:

• chrM-13513-G-C
• rs267606897
• ENST00000361567.2:c.1177G>C
• MT-ND5 p.Asp393His

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM2PM5PP3

The ENST00000361567.2(MT-ND5):c.1177G>C (p.Asp393His) variant causes a missense change involving the alteration of a conserved nucleotide. Note: ENST00000361567.2 is not a MANE Select or MANE Plus Clinical transcript for MT-ND5; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant is observed in the Mitomap database at a frequency of 0.000015 (AC=1). In-silico predictor (AlphaMissense) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.29). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D393N: Pathogenic (ClinVar VariationId 9702, 3 stars)

• Frequency: Mitomap GenBank: 𝑓 0.000015 (AC: 1)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.83
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 9.29
• Publications: 1 publications found

Genes affected

MT-ND5 (HGNC:7461): (NADH dehydrogenase subunit 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Jul 2025]

MT-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Extremely rare in Mitomap (AF <0.01%) — PM2; Mitomap AF = 0.000015 — extremely rare (PM2).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D393N: Pathogenic (ClinVar VariationId 9702, 3 stars)
	PP3Computational evidence supports damaging effect		Mitochondrial protein-coding: Apogee2 ≥0.5 — computational evidence of damage (PP3); Apogee2 = 0.834 (threshold ≥0.5).; HmtVar = 0.890 (threshold ≥0.35).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MT-ND5 ENST00000361567.2	TSL:6	c.1177G>C p.Asp393His	missense	Exon 1 of 1	Prot: ENSP00000354813.2 UniProt:

MT-ND5 ENST00000361567.2

TSL:6

HGVSc / HGVSpc.1177G>Cp.Asp393His

Exon rankExon 1 of 1

missense

Prot: ENSP00000354813.2UniProt: P03915

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Mitochondrial 1 source Mitochondrial genome frequencies
Mitomap GenBank	AF: 0.000015	AC:1	Hom:	AN:	Cov:

Showing 1 sources

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaMissense	Pathogenic	0.98
Apogee2	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.018	T
DEOGEN2	Benign	0.24	T
Hmtvar	Pathogenic	0.89
LIST_S2	Pathogenic	0.98	D
Mutation Taster	N/A	14/86	disease causing
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	9.3
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.91
VESM-3B	Benign	-13

Showing 13 of 13 scores

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs267606897;

hg19: chrM-13514;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar