19-1391006-G-A

Position:

chr19-1391006-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The ENST00000233627.14(NDUFS7):c.364G>A(p.Val122Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

NDUFS7
ENST00000233627.14 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.43

Variant links:

Genes affected

NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

NDUFS7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial (size 174) in uniprot entity NDUS7_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in ENST00000233627.14

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 19-1391006-G-A is Pathogenic according to our data. Variant chr19-1391006-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1391006-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-1391006-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS7	NM_024407.5 linkuse as main transcript	c.364G>A	p.Val122Met	missense_variant	5/8	ENST00000233627.14	NP_077718.3
NDUFS7	NM_001363602.2 linkuse as main transcript	c.364G>A	p.Val122Met	missense_variant	5/8		NP_001350531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14 linkuse as main transcript	c.364G>A	p.Val122Met	missense_variant	5/8	1	NM_024407.5	ENSP00000233627	P1	O75251-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

249914

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135460

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

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:

0.0000887

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000856

AC:

125

AN:

1460992

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726836

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2024	In vitro functional study in yeast indicated that the V119M variant in NUKM, that corresponds to the V122M variant in NDUFS7 gene in humans, impairs complex I activity (PMID: 11004438); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10330338, 22033105, 14749350, 29144225, 31014978, 30369941, 29977174, 15269216, 18513682, 15576052, 10360771, 36557887, 35718301, 11004438) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 122 of the NDUFS7 protein (p.Val122Met). This variant is present in population databases (rs104894705, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive Leigh syndrome (PMID: 10330338, 10360771, 30369941). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7681). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFS7 function (PMID: 11004438). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NDUFS7: PM2, PM3, PP3, PP4, PS3:Supporting -

Mitochondrial complex 1 deficiency, nuclear type 3

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 24, 2004	- -

Leigh syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 01, 2023

Variant summary: NDUFS7 c.364G>A (p.Val122Met) results in a conservative amino acid change located in the NADH:ubiquinone oxidoreductase-like, 20kDa subunit (IPR006137) of the encoded protein sequence. The variant allele was found at a frequency of 5.6e-05 in 249914 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NDUFS7 causing Leigh Syndrome (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.364G>A has been reported in the literature in multiple individuals affected with Complex 1 deficiency and Leigh Syndrome (examples: Triepels_1999 and Theunissen_2018). 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. V119M in NUKM protein of Y. lipolytica corresponds to V122M variant in NDUFS7 gene in humans, this variant impaired complex1 activity in vitro (Ahlers_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as 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

0.93

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

.;D;T;D;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.5

H;H;.;.;H;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.7

D;D;.;D;D;.;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;.;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

.;D;.;D;.;.;.

Vest4

0.95

MVP

0.99

MPC

1.4

ClinPred

0.67

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.93

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

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