11-67612225-C-T

Variant names:

• chr11-67612225-C-T
• rs121913659
• NM_007103.4:c.1268C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007103.4(NDUFV1):​c.1268C>T​(p.Thr423Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T423T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFV1 NM_007103.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 4.79
• Publications: 22 publications found

Genes affected

NDUFV1 (HGNC:7716): (NADH:ubiquinone oxidoreductase core subunit V1) The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

NDUFV1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-67612225-C-T is Pathogenic according to our data. Variant chr11-67612225-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007103.4. 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
	NDUFV1	NM_007103.4	MANE Select	c.1268C>T	p.Thr423Met	missense	Exon 9 of 10	NP_009034.2
	NDUFV1	NM_001166102.2		c.1241C>T	p.Thr414Met	missense	Exon 9 of 10	NP_001159574.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFV1	ENST00000322776.11	TSL:1 MANE Select	c.1268C>T	p.Thr423Met	missense	Exon 9 of 10	ENSP00000322450.6
	NDUFV1	ENST00000529927.5	TSL:1	c.1241C>T	p.Thr414Met	missense	Exon 9 of 10	ENSP00000436766.1
	NDUFV1	ENST00000647561.1		c.1268C>T	p.Thr423Met	missense	Exon 10 of 11	ENSP00000497587.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151768 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251318 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151768 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74088

African (AFR) AF: 0.0000968 AC: 4 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000186 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 4 Pathogenic:8

Jun 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1268C>T;p.(Thr423Met) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 14056 ; PMID: 30090137; 10080174) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26345448) - PS3_supporting. The variant is present at low allele frequencies population databases (rs121913659– gnomAD 0.0003295%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Thr423Met) was detected in trans with a Pathogenic variant (PMID: 30090137; 10080174) and found as compound heterozygous with another variant classified as Pathogenic (knowing the phase of each variant), in the analyzed case - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 10080174) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014056, PMID:10080174, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 14662656, PS3_M).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10080174, PM3_M). and co-segregated with Mitochondrial complex I deficiency, nuclear type 4 in multiple affected family members (PMID: 10080174, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.859, PP3_P). A missense variant is a common mechanism associated with Mitochondrial complex I deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Dec 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NDUFV1 c.1268C>T; p.Thr423Met variant (rs121913659, ClinVar Variation ID: 14056) has been reported homozygous and compound heterozygous in the literature in multiple individuals with mitochondrial complex I deficiency (Liu 2019, Schuelke 1999, Zanette 2021). This variant is only observed on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.859). One study found this variant protein to have strongly impaired enzyme function (Varghese 2015). Based on available information this variant is considered to be pathogenic. REFERENCES Liu P et al. Reanalysis of Clinical Exome Sequencing Data. N Engl J Med. 2019 Jun 20;380(25):2478-2480. PMID: 31216405. Schuelke M et al. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet. 1999 Mar;21(3):260-1. PMID: 10080174. Varghese F et al. Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. Hum Mol Genet. 2015 Nov 15;24(22):6350-60. PMID: 26345448. Zanette V et al. NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms. Genet Mol Biol. 2021 Nov 19;44(4):e20210149. PMID: 34807224.

Aug 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2024

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP1 supporting, PP3 supporting

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial complex I deficiency Pathogenic:2

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 08, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:2

Dec 31, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

May 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17383918, 19041632, 17289351, 18435906, 18353897, 29948731, 30090137, 11579423, 20153825, 11181577, 16120313, 34807224, 31665838, 10080174, 21696386, 17600689, 10649489, 19703648, 19255735, 15901599, 18295330, 10330338, 29395179, 24704045, 11112787, 14662656, 16213125, 24524415, 30429455, 15981016, 22033105, 10862082, 10885663, 23631824, 22142868, 30055843, 26345448, 31216405, 33083013)

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 423 of the NDUFV1 protein (p.Thr423Met). This variant is present in population databases (rs121913659, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 10080174, 22644603, 30090137, 31665838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14056). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDUFV1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Leigh syndrome Pathogenic:1

Nov 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NDUFV1 c.1268C>T (p.Thr423Met) results in a non-conservative amino acid change located in the NADH-ubiquinone oxidoreductase 51kDa subunit, iron-sulphur binding domain (IPR019575) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251318 control chromosomes. c.1268C>T has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple individuals affected with Leigh Syndrome (example, PMID 33083013, 34716721, 10080174). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID 26345448). The most pronounced variant effect results in absence of detectable complex I in an apparently homozygous (by cDNA sequencing), but compound heterozygous genotype due to a nonsense variant on the other allele that was not expressed. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.88		Gain of sheet (P = 0.1208)
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121913659; hg19: chr11-67379696;