chrM-13513-G-A

Variant names:

• chrM-13513-G-A
• rs267606897
• ENST00000361567.2:c.1177G>A
• MT-ND5 p.Asp393Asn

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PM2PM5PP3PP5_Very_Strong

The unassigned_transcript_4815(ND5):c.1177G>A (p.Asp393Asn) variant causes a missense change involving the alteration of a conserved nucleotide. Note: unassigned_transcript_4815 is not a MANE Select or MANE Plus Clinical transcript for ND5; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. No reliable population frequency data is available for this variant in the Mitomap database. 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). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D393G: Likely_pathogenic (ClinVar VariationId 155889, 3 stars)

• Frequency: Mitomap GenBank: Absent
• Consequence: ND5 unassigned_transcript_4815 missense
• Scores: Apogee2 Pathogenic 0.92
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:2 Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome / negative association w Carotid Atherosclerosis
• 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: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from Mitomap — mitochondrial genome is well-covered; PM2; Absent from Mitomap — mitochondrial genome is well-covered; absence means frequency ≈ 0 (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.D393G: Likely_pathogenic (ClinVar VariationId 155889, 3 stars)
	PP3Computational evidence supports damaging effect		Mitochondrial protein-coding: Apogee2 ≥0.5 — computational evidence of damage (PP3); Apogee2 = 0.918 (threshold ≥0.5).; HmtVar = 0.870 (threshold ≥0.35).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (13/13 total P/LP).

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>A p.Asp393Asn	missense	Exon 1 of 1	Prot: ENSP00000354813.2 UniProt:

MT-ND5 ENST00000361567.2

TSL:6

HGVSc / HGVSpc.1177G>Ap.Asp393Asn

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
Global population databases 1 source Large-scale international reference populations
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000219	AC:1	Hom:0	AN:45694	Cov:
Mitochondrial 2 sources Mitochondrial genome frequencies
Gnomad homoplasmic Warning	AF: 0.0	AC:0	Hom:	AN:56431	Cov:
Gnomad heteroplasmic Warning	AF: 0.0	AC:0	Hom:	AN:56431	Cov:

Showing 3 sources

Tested, but no data found:Mitomap GenBank

Mitomap

Disease(s): Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome / negative association w Carotid Atherosclerosis

Status: Cfrm [P]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Leigh syndrome (4)
3	-	-	Mitochondrial disease (3)
3	-	-	not provided (3)
2	-	-	MELAS syndrome (3)
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)
1	-	-	Primary Mitochondrial Disorders (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaMissense	Pathogenic	0.92
Apogee2	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.16	D
DEOGEN2	Benign	0.41	T
Hmtvar	Pathogenic	0.87
LIST_S2	Uncertain	0.86	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Pathogenic	9.3
PROVEAN	Pathogenic	-4.5	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.89
VESM-3B	Benign	-12

Showing 12 of 12 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;

COSMIC: COSV104419742;

COSMIC: COSV104419742;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar