rs199974018

Variant names:

• chrM-12811-T-C
• rs199974018
• ENST00000361567.2:c.475T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The m.12811T>C (p. Y159H) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 17, 2023. This variant has not been reported in the medical literature as an individual cause of primary mitochondrial disease to our knowledge. However, there are nine cases reported that have this variant and the common Leber Hereditary Optic Neuropathy (LHON) variant, m.11778G>A, and one case with this variant and the m.3460G>A common LHON variant (PMIDs: 17406640, 17434142, 19026397). While this variant has been reported to be a modifier or secondary variant for LHON, assessment of such variants is outside the scope of this curation. The computational predictor APOGEE gives a consensus rating of 0.32 (Min=0, Max=1), supporting a neutral effect of this variant on function (BP4). This variant is present in population databases including MITOMAP’s GenBank sequences (674/59,389; 1.135%), in the Helix dataset (1,274/195,983; 0.650%; includes 1274 homoplasmic occurrences and 14 heteroplasmic occurrences and seen in haplogroups H, M, A, K, W, D, L2, T), and in gnomAD v3.1.2 (328/56,429; 0.581%; includes 328 homoplasmic occurrences across individuals of East Asian, European (non-Finnish), Latino, and South Asian descent; BA1). 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 benign 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 April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CV65510/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.011 (AC: 681)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.012
• Clinical Significance: Benign reviewed by expert panel U:1 B:2 O:1 Possible-LHON-factor
• Conservation: PhyloP100: -1.37
• Publications: 30 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: G2P, Orphanet
• 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: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.475T>C	p.Tyr159His	missense	Exon 1 of 1	ENSP00000354813.2	P03915

Frequencies

Mitomap GenBank AF: 0.011 AC: 681

Gnomad homoplasmic AF: 0.0058 AC: 328 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Alfa AF: 0.000837 Hom.: 9

Mitomap

Disease(s): Possible-LHON-factor

Status: Reported-[B]

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial disease (1)
-	1	-	not provided (1)
-	-	-	Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.012
Hmtvar	Benign	0.17
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
DEOGEN2	Benign	0.029	T
LIST_S2	Benign	0.45	T
MutationAssessor	Benign	0.68	N
PhyloP100		-1.4
PROVEAN	Benign	-1.8	N
Sift4G	Benign	0.35	T
GERP RS		-1.3
Varity_R		0.43
Mutation Taster		=84/16	polymorphism

Other links and lift over

dbSNP: rs199974018; hg19: chrM-12812;