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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
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.706G>A	p.Ala236Thr	missense	Exon 1 of 1	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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (3)
1	-	-	Leber optic atrophy (1)
1	-	-	Leigh syndrome due to mitochondrial complex I deficiency (1)
1	-	-	MERRF syndrome (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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;