rs587776440

Positions:

• chrM-13514-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

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

• Frequency: Mitomap GenBank: Absent
• Consequence: ND5 missense
• Scores: Apogee2 Pathogenic 0.96
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:2 Leigh-Disease-/-MELAS-/-Ca2+-downregulation
• Conservation: PhyloP100: 8.67

Genes affected

ND5 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-13514-A-G is Pathogenic according to our data. Variant chrM-13514-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155889.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND5	unassigned_transcript_4816	c.1178A>G	p.Asp393Gly	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

Leigh-Disease-/-MELAS-/-Ca2+-downregulation

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 17, 2019	The NC_012920.1:m.13514A>G (YP_003024036.1:p.Asp393Gly) variant in MTND5 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

The m.13514A>G (p.D393G) variant in MT-ND5 has been reported in at least 12 unrelated individuals with primary mitochondrial disease with onset ranging from childhood to adulthood and features variably consistent with Leigh syndrome and MELAS, as well as hypertrophic cardiomyopathy, optic atrophy, and neuropathy (PS4_moderate; PMIDs: 26341968, 25974876, 32504279, 20972245, 23847141, 21712854, 15576045, 14684687, 11198278). Heteroplasmy levels in affected individuals ranged from 55-70% in muscle, 12-55% in fibroblasts, 4-50% in blood, and 90% heart. This variant has been identified as a de novo occurrence in at least two probands with primary mitochondrial disease (PM6_supporting; PMIDs: 14684687, 11198278). 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). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by this Expert Panel – m.13513G>A (p. D393N, PM5). Cybrid studies showed a tight correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 11198278). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PM5, PS3_supporting, PP3. -

MELAS syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.96
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.085	D
DEOGEN2	Benign	0.28	T
LIST_S2	Uncertain	0.95	D
MutationAssessor	Pathogenic	3.7	H
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776440; hg19: chrM-13515;