ENST00000361681.2:c.76A>G

Variant names:

• chrM-14598-T-C
• rs1057518882
• ENST00000361681.2:c.76A>G

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The m.14598T>C (p.I26V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on August 14, 2023. There are no individuals with this variant reported in the medical literature to our knowledge. There are two prior reports in ClinVar for this variant, however details are not provided precluding consideration of these cases for this curation. As such, there are no reported de novo occurrences or large families to consider for evidence of variant segregation. This variant is present in population databases including in Mitomap GenBank sequences (7/61,168 (0.012%) and seen across five top level (single letter) haplogroups with European, Asian, and African ancestry), Helix database (26/195,983 sequences (0.013%), in addition to three heteroplasmic occurrences and seen across six top level haplogroups with European, Asian, and African ancestry), and gnomAD v3.1.2 (9/56,416 sequences (0.016%) in addition to three heteroplasmic occurrences and seen across seven top level haplogroups with European, Asian, and African ancestry). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.31 (Min=0, Max=1; APOGEE2 scores on 0.0499), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other key functional assays reported for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two expert panel members felt likely benign was the more appropriate classification (compared to five who agreed with uncertain significance). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16043602/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 7)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Benign 0.050
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1 PD-/-LS
• Conservation: PhyloP100: 0.263
• Publications: 4 publications found

Genes affected

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND6	ENST00000361681.2	TSL:6	c.76A>G	p.Ile26Val	missense	Exon 1 of 1	ENSP00000354665.2
	MT-CYB	ENST00000361789.2	TSL:6	c.-149T>C		upstream_gene	N/A	ENSP00000354554.2
	MT-TE	ENST00000387459.1	TSL:6	n.*76A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.00010 AC: 7

Gnomad homoplasmic AF: 0.00016 AC: 9 AN: 56425

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56425

Alfa AF: 0.000223 Hom.: 1

Mitomap

Disease(s): PD-/-LS

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Parkinsonian disorder;C0456909:Blindness Pathogenic:1

Jul 15, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial disease Uncertain:1

Aug 14, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.14598T>C (p.I26V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on August 14, 2023. There are no individuals with this variant reported in the medical literature to our knowledge. There are two prior reports in ClinVar for this variant, however details are not provided precluding consideration of these cases for this curation. As such, there are no reported de novo occurrences or large families to consider for evidence of variant segregation. This variant is present in population databases including in Mitomap GenBank sequences (7/61,168 (0.012%) and seen across five top level (single letter) haplogroups with European, Asian, and African ancestry), Helix database (26/195,983 sequences (0.013%), in addition to three heteroplasmic occurrences and seen across six top level haplogroups with European, Asian, and African ancestry), and gnomAD v3.1.2 (9/56,416 sequences (0.016%) in addition to three heteroplasmic occurrences and seen across seven top level haplogroups with European, Asian, and African ancestry). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.31 (Min=0, Max=1; APOGEE2 scores on 0.0499), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other key functional assays reported for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two expert panel members felt likely benign was the more appropriate classification (compared to five who agreed with uncertain significance). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4.

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14598T>C (YP_003024037.1:p.Ile26Val) variant in MTND6 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS4, BP6

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.050
Hmtvar	Pathogenic	0.68
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.58	T
DEOGEN2	Benign	0.22	T
LIST_S2	Benign	0.67	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.26
PROVEAN	Benign	-0.62	N
Sift	Uncertain	0.011	D
Sift4G	Benign	0.39	T
GERP RS		-0.56
Varity_R		0.40

Other links and lift over

dbSNP: rs1057518882; hg19: chrM-14599; COSMIC: COSV62378546; COSMIC: COSV62378546;