rs397515612

Positions:

• chrM-3376-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: ND1 missense
• Scores: Apogee2 Pathogenic 0.94
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1 LHON-MELAS-overlap
• Conservation: PhyloP100: 6.32

Genes affected

ND1 (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
ND1	unassigned_transcript_4790	c.70G>A	p.Glu24Lys	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-MELAS-overlap

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jun 30, 2022

The m.3376G>A (p.E24K) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID: 15657614). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids or single fiber studies 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 Mitochondrial Disease Variant Curation Expert Panel on February 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria (PMID: 32906214): PS2_supporting, PM2_supporting, BP4. -

Leber optic atrophy Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.94
Hmtvar	Pathogenic	0.94
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
DEOGEN2	Uncertain	0.46	T
LIST_S2	Uncertain	0.94	D
MutationAssessor	Pathogenic	4.2	H
PROVEAN	Uncertain	-3.6	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515612; hg19: chrM-3377;