rs121913660

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_007103.4(NDUFV1):c.1022C>T(p.Ala341Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NDUFV1
NM_007103.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 0.999

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-67611511-C-T is Pathogenic according to our data. Variant chr11-67611511-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.34843192). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV1	NM_007103.4 link	c.1022C>T	p.Ala341Val	missense_variant	Exon 7 of 10	ENST00000322776.11	NP_009034.2	P49821-1E5KNH5
NDUFV1	NM_001166102.2 link	c.995C>T	p.Ala332Val	missense_variant	Exon 7 of 10		NP_001159574.1	P49821-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV1	ENST00000322776.11 link	c.1022C>T	p.Ala341Val	missense_variant	Exon 7 of 10	1	NM_007103.4	ENSP00000322450.6		P49821-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249160

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134690

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461042

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000549

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000596

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 4

Pathogenic:3

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1022C>T(p.Ala341Val) in NDUFV1 gene has been reported previously in homozygous state in multiple individuals with mitochondrial disorders (Zanette V, et al., 2021, Varghese F, et al., 2015, Bugiani M, et al., 2004). The c.1022C>T(p.Ala341Val) variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretations as Uncertain Significane/ Likely Pathogenic/ Pathogenic. Multiple lines of computational evidence (Polyphen-possibly damaging, SIFT-dmaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Ala at position 341 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Ala341Val in NDUFV1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the NDUFV1 protein (p.Ala341Val). This variant is present in population databases (rs121913660, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 10080174, 15576045). ClinVar contains an entry for this variant (Variation ID: 14058). 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 not expected to disrupt NDUFV1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NDUFV1 function (PMID: 14662656, 26345448). 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. -

Jul 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Grad et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10330338, 23562761, 26345448, 21696386, 29948731, 22310368, 17162199, 18991197, 11579423, 19041632, 14662656, 26004627, 10080174, 34426522, 15576045) -

Leigh syndrome

Pathogenic:1

Feb 28, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NDUFV1 c.1022C>T (p.Ala341Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249160 control chromosomes (gnomAD). c.1022C>T has been reported in the literature in homozygous individuals affected with isolated complex I deficiency (Schuelke_1999, Bugiani_2004). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions. Specifically, an animal study utilizing transgenic strains of C. elegans demonstrated the variant to be damaging (Grad_2004), while another study utilizing a yeast model system (Y. lipolytica) concluded the variant behaved normally (Varghese_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mitochondrial complex I deficiency

Uncertain:1

Mar 01, 1999

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;T;.;T

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.56

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.35

T;T;T;T;T

MetaSVM

Uncertain

-0.012

MutationAssessor

Pathogenic

3.3

M;M;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.0

.;D;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0070

.;D;D;D;D

Sift4G

Uncertain

0.024

.;D;D;D;D

Polyphen

0.73

P;P;.;P;P

Vest4

0.76, 0.73, 0.50, 0.78

MVP

0.73

MPC

0.50

ClinPred

0.69

GERP RS

1.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.21

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over