rs150966634

chr11-67611972-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007103.4(NDUFV1):c.1156C>T(p.Arg386Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,798 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: NDUFV1 NM_007103.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.39

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 18 ACMG points.

• PM1: In a helix (size 18) in uniprot entity NDUV1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_007103.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-67611973-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1465562.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 11-67611972-C-T is Pathogenic according to our data. Variant chr11-67611972-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFV1	NM_007103.4	c.1156C>T	p.Arg386Cys	missense_variant	8/10	ENST00000322776.11
NDUFV1	NM_001166102.2	c.1129C>T	p.Arg377Cys	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV1	ENST00000322776.11	c.1156C>T	p.Arg386Cys	missense_variant	8/10	1	NM_007103.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.000123 AC: 31 AN: 251360 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135850

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151982 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74236

Gnomad4 AFR AF: 0.0000242

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

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A homozygous missense variant was identified, NM_007103.3(NDUFV1):c.1156C>T in exon 8 of 10 of the NDUFV1 gene. This substitution is predicted to create a major amino acid change from arginine to cysteine at position 386 of the protein, NP_009034.2(NDUFV1):p.(Arg386Cys). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the NADH-ubiquinone oxidoreductase-F iron-sulfur binding region (PDB). In silico software predicts this variant to be damaging (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a global allele frequency of 0.01% (31 heterozygotes; 0 homozygotes), and is enriched in the South Asian population at a frequency of 0.09%. An alternative change to histidine at the same residue has also been reported in the gnomAD database at a frequency of 0.005%. The variant has previously been reported as pathogenic in patients with mitochondrial complex I deficiency and has been shown to segregate with the disease in families (ClinVar, Breningstall, G. et al. (2008), Srivastava, A. et al. (2018), Ortega-Recalde, O. et al. (2013), Marin, S. et al. (2013)). A different variant in the same codon resulting in a change to histidine has also been shown to cause mitochondrial complex I deficiency (ClinVar, Vilain, C. et al. (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Likely pathogenic, criteria provided, single submitter	research	Bruce Lefroy Centre, Murdoch Childrens Research Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R386C in NDUFV1 (NM_007103.3) has been previously reported in multiple affected individuals. It is a founder mutation in South Asians (Srivastava A et al, 2018). The missense variant c.1156C>T (p.R386C) in NDUFV1 (NM_007103.4) is observed in 28/30616 (0.0915%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. It has been classified in the ClinVar database as Likely Pathogenic/Pathogenic. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R386C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 386 of NDUFV1 is conserved in all mammalian species. The nucleotide c.1156 in NDUFV1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. As it is a Founder mutation, it has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2020	Published functional studies demonstrate a damaging effect; the R386C variant results in an impaired complex I activity with decreased flavin mononucleotide (FMN) content (Varghese et al., 2015).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26684010, 27126960, 28441825, 33182419, 23266820, 19073330, 26345448, 23562761, 26024641, 29272804, 29353736, 29948731, 30777920, 29976978, 32180488) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the NDUFV1 protein (p.Arg386Cys). This variant is present in population databases (rs150966634, gnomAD 0.08%). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 26024641, 32180488, 33182419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 419230). 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%. Studies have shown that this missense change alters NDUFV1 gene expression (PMID: 33182419). This variant disrupts the p.Arg386 amino acid residue in NDUFV1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20818383, 26345448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The homozygous p.Arg386Cys variant in NDUFV1 was identified by our study in 6 individuals with primary microcephaly. This variant has been reported in the literature in the case of one homozygous affected female proband and her affected brother. It has also been seen in two compound heterozygous affected brothers alongside the likely pathogenic c.914-8G_947del mutation (Breningstall et al. 2008, PMID: 19073330; Ortega-Recalde et al. 2013 PMID: 23562761). A different pathogenic variant, p.Arg386His, has been identified at this amino acid residue, further provding evidence for pathogenicity. This variant has been identified in 0.08% (26/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150966634). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3, PM5 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.3	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	D;D;.;D;D
Vest4		0.98, 0.98, 0.95, 0.98
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150966634; hg19: chr11-67379443; COSMIC: COSV100508516; COSMIC: COSV100508516;