rs121913659

chr11-67612225-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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. 12/21 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:12
• Conservation: PhyloP100: 4.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 14056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67612225-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFV1	NM_007103.4	c.1268C>T	p.Thr423Met	missense_variant	9/10	ENST00000322776.11
NDUFV1	NM_001166102.2	c.1241C>T	p.Thr414Met	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV1	ENST00000322776.11	c.1268C>T	p.Thr423Met	missense_variant	9/10	1	NM_007103.4	P1

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

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251318 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000497

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

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 07, 2019	- -

Mitochondrial complex I deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 08, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2021	Published functional studies demonstrate a damaging effect: absent or reduced Complex I activity in a yeast-based assay and in C. elegans (Grad et al., 2004; Varghese et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17383918, 19041632, 17289351, 18435906, 18353897, 29948731, 30090137, 11579423, 20153825, 11181577, 16120313, 31665838, 10080174, 21696386, 26345448, 17600689, 10649489, 19703648, 19255735, 15901599, 18295330, 10330338, 29395179, 24704045, 11112787, 14662656, 16213125, 24524415, 30429455, 15981016, 22033105, 10862082, 10885663, 23631824, 22142868, 30055843, 31216405, 33083013) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 28, 2022

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 v4.3

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;D;D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.80	T
Polyphen		1.0	D;D;.;D;D
Vest4		0.93, 0.92, 0.88, 0.94
MutPred		0.88		Gain of sheet (P = 0.1208);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913659; hg19: chr11-67379696;