rs387906425

Positions:

• chrM-13730-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND5 missense
• Scores: Apogee2 Pathogenic 0.96
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 LHON
• Conservation: PhyloP100: 9.29

Genes affected

ND5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND5	unassigned_transcript_4816	c.1394G>A	p.Gly465Glu	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

LHON

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1993	- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Nov 13, 2023

The m.13730G>A (p.G465E) variant in MT-ND5 has been reported in one individual from one family to date (PMID: 8213825), in a male with Leber Hereditary Optic Neuropathy (LHON). The variant was present at 80% heteroplasmy in blood. The variant was presumed to have occurred de novo as it was absent in blood from his mother, maternal grandmother, and two maternal uncles (PMID: 8213825), however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83, which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.96
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.092	D
DEOGEN2	Uncertain	0.51	D
LIST_S2	Uncertain	0.94	D
MutationAssessor	Pathogenic	4.6	H
PROVEAN	Pathogenic	-7.2	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906425; hg19: chrM-13731;