rs267606898

Variant names:

• chrM-13042-G-A
• rs267606898
• ENST00000361567.2:c.706G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.13042G>A (p.A236T) variant in MT-ND5 has been reported in six unrelated individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and features variably consistent CPEO, LHON, MERRF/MELAS, Leigh-like syndrome (PS4_moderate; PMIDs: 15767514; 17400793; 31996177; 16816025). This variant segregated with disease in a family with LHON as the proband's heteroplasmy was 41% in urine and his affected sister had the variant present at 39% in urine and 91% in muscle. There were unaffected sisters (heteroplasmy levels of 4% and 20% in urine) as well as an unaffected brother with the variant present at 43% urine. In another family, this variant segregated with Leigh syndrome in the proband (heteroplasmy level in in blood was 77%, in muscle was 84%, in fibroblasts was 86%); the healthy mother harbored the variant in hair (25%) and blood (11%); and the proband’s maternal grandmother was found to have the variant at < 2% in blood and between 4-6% in muscle (PP1_moderate, PMIDs: 16816025 17400793). There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is only one occurrence in the GenBank dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.85 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 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 June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120633/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Pathogenic 0.89
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 O:1 Optic-neuropathy/-retinopathy/-LD
• Conservation: PhyloP100: 7.46
• Publications: 7 publications found

Genes affected

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.706G>A	p.Ala236Thr	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.706G>A	p.Ala236Thr	missense_variant	Exon 1 of 1	6		ENSP00000354813.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Optic-neuropathy/-retinopathy/-LD

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:2 Other:1

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009703). Should be validated by an alternate clinical test Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

MERRF syndrome Pathogenic:1

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Pathogenic:1

Jun 30, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.13042G>A (p.A236T) variant in MT-ND5 has been reported in six unrelated individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and features variably consistent CPEO, LHON, MERRF/MELAS, Leigh-like syndrome (PS4_moderate; PMIDs: 15767514; 17400793; 31996177; 16816025). This variant segregated with disease in a family with LHON as the proband's heteroplasmy was 41% in urine and his affected sister had the variant present at 39% in urine and 91% in muscle. There were unaffected sisters (heteroplasmy levels of 4% and 20% in urine) as well as an unaffected brother with the variant present at 43% urine. In another family, this variant segregated with Leigh syndrome in the proband (heteroplasmy level in in blood was 77%, in muscle was 84%, in fibroblasts was 86%); the healthy mother harbored the variant in hair (25%) and blood (11%); and the proband’s maternal grandmother was found to have the variant at < 2% in blood and between 4-6% in muscle (PP1_moderate, PMIDs: 16816025 17400793). There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is only one occurrence in the GenBank dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.85 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 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 June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting.

Leber optic atrophy Pathogenic:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.13042G>A (YP_003024036.1:p.Ala236Thr) 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, PM8, PM9, PM10

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.89
Hmtvar	Pathogenic	0.78
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
DEOGEN2	Benign	0.22	T
LIST_S2	Benign	0.82	T
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.5
PROVEAN	Uncertain	-3.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.5
Varity_R		0.75
Mutation Taster		=50/50

Other links and lift over

dbSNP: rs267606898; hg19: chrM-13043; COSMIC: COSV62292993; COSMIC: COSV62292993;