Genetic Variant MT-ND5:p.Asp393Asn (chrM-13513-GAC-AAT) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM2PM5

The unassigned_transcript_4815(ND5):c.1177_1179delGACinsAAT (p.Asp393Asn) variant causes a missense change. 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. 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.D393G: Likely_pathogenic (ClinVar VariationId 155889, 3 stars)

Frequency

Mitomap GenBank:

Absent

Consequence

ND5
unassigned_transcript_4815 missense

Scores

Clinical Significance

Not reported in ClinVar

No linked disesase in Mitomap

Conservation

PhyloP100: 9.29

Publications

0 publications found

Variant links:

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

MT-ND5 links:

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new If you want to explore the variant's impact on the transcript unassigned_transcript_4815, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Show applied only (3)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	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)

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.1177_1179delGACinsAAT p.Asp393Asn	missense	N/A	Prot: ENSP00000354813.2 UniProt: P03915

MT-ND5 ENST00000361567.2

TSL:6

HGVSc / HGVSpc.1177_1179delGACinsAATp.Asp393Asn

Exon rankN/A

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

Showing 0 sources

Tested, but no data found:Mitomap GenBank

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.3

Showing 1 of 1 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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Mitomap

ClinVar

Computational Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence