NM_007103.4:c.119G>A

Variant names:

• chr11-67608442-G-A
• rs141502688
• NM_007103.4:c.119G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_007103.4(NDUFV1):​c.119G>A​(p.Arg40Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NDUFV1 NM_007103.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.40

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-67608442-G-A is Pathogenic according to our data. Variant chr11-67608442-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521516.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV1	NM_007103.4	c.119G>A	p.Arg40Gln	missense_variant	Exon 2 of 10	ENST00000322776.11	NP_009034.2
NDUFV1	NM_001166102.2	c.92G>A	p.Arg31Gln	missense_variant	Exon 2 of 10		NP_001159574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV1	ENST00000322776.11	c.119G>A	p.Arg40Gln	missense_variant	Exon 2 of 10	1	NM_007103.4	ENSP00000322450.6

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.0000755 AC: 19 AN: 251496 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000447

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: 0.0000153

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000328

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: 0.000113 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Mar 04, 2025

GeneDx

Significance: Likely 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 35482246) -

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the NDUFV1 protein (p.Arg40Gln). This variant is present in population databases (rs141502688, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with NDUFV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 521516). 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 95%. This variant disrupts the p.Arg40 amino acid residue in NDUFV1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35482246). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases Uncertain:1

Jan 23, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1

Feb 23, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.69	D
PROVEAN	Benign	0.40	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.091	T
MutPred		0.49		Loss of sheet (P = 0.0054);
MVP		0.98
ClinPred		0.87	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs141502688; hg19: chr11-67375913; COSMIC: COSV59596446; COSMIC: COSV59596446;