ClinVar Genomic variation as it relates to human health
NM_007103.4(NDUFV1):c.1157G>A (p.Arg386His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007103.4(NDUFV1):c.1157G>A (p.Arg386His)
Variation ID: 496918 Accession: VCV000496918.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 67611973 (GRCh38) [ NCBI UCSC ] 11: 67379444 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 2, 2018 Oct 13, 2024 Oct 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007103.4(NDUFV1):c.1157G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_007103.4:c.1157G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009034.2:p.Arg386His missense NM_001166102.2:c.1130G>A NP_001159574.1:p.Arg377His missense NC_000011.10:g.67611973G>A NC_000011.9:g.67379444G>A NG_013353.1:g.10122G>A - Protein change
- R386H, R377H
- Other names
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- Canonical SPDI
- NC_000011.10:67611972:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOC126861242 | - | - | - | GRCh38 | - | 128 |
NDUFV1 | - | - |
GRCh38 GRCh37 |
354 | 504 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV001731801.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2024 | RCV000592779.15 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV001783094.9 | |
NDUFV1-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2022 | RCV004530649.1 |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2024 | RCV004760638.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700634.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
Sex: mixed
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Likely pathogenic
(Mar 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570273.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This NDUFV1 variant (rs536758576) is rare (<0.1%) in a large population dataset (gnomAD: 14/282690 total alleles; 0.005%; no homozygotes) and has been reported in ClinVar. … (more)
This NDUFV1 variant (rs536758576) is rare (<0.1%) in a large population dataset (gnomAD: 14/282690 total alleles; 0.005%; no homozygotes) and has been reported in ClinVar. It has been reported in a homozygous and compound heterozygous state in individuals with mitochondrial complex I deficiency. A different pathogenic variant, p.Arg386Cys, has also been reported at this amino acid position8. Three bioinformatic tools queried predict that the p.(Arg386His) substitution would be damaging, and the arginine residue at this position is strongly conserved across the vertebrate species assessed. This substitution is predicted to disrupt the protein–protein interactions that facilitate Fe–S cluster buffering and showed evidence of impaired complex I activity in a yeast model system. Bioinformatic analysis predicts that this variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant alone is not expected to cause disease. We consider this variant to be likely pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573033.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense changes are a common disease-causing mechanism. The variant was found to in trans with other pathogenic variant (3billion dataset). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.67). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000496918 ) and different missense changes at the same codon (p.Arg386Cys, p.Arg386Leu; ClinVar ID: VCV000419230 , VCV001465562 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Lactic acidosis (present)
Zygosity: Single Heterozygote
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Pathogenic
(Jun 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983621.2
First in ClinVar: Oct 30, 2021 Last updated: Jul 29, 2023 |
Comment:
Variant summary: NDUFV1 c.1157G>A (p.Arg386His) results in a non-conservative amino acid change located in the iron-sulphur binding domain (IPR019575) of the encoded protein sequence. Five … (more)
Variant summary: NDUFV1 c.1157G>A (p.Arg386His) results in a non-conservative amino acid change located in the 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 3.6e-05 in 251346 control chromosomes (gnomAD). c.1157G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Leigh Syndrome/complex I deficiency who have been comprehensively genotyped (sequencing/homozygosity mapping approaches) (e.g. Calvo_2010, Swalwell_2011, Vilain_2012, French_2022, Tang_2022). These data indicate that the variant is very likely to be associated with disease. An experimental study evaluating the impact of the variant on protein function in a yeast model system reported decreased flavin content, intermediate complex 1 activity, and slight destablilization; however, these findings do not necessarily allow for convincing conclusions about the variant effect in vivo due to the nature of the experimental system employed (Varghese_2015). Another variant affecting the same amino acid (c.1156C>T, p.Arg386Cys) has also been observed in affected individuals and is classified as pathogenic/likely pathogenic in ClinVar, suggesting that R386 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 25615419, 20818383, 23562761, 29976978, 21364701, 26345448, 21696386, 35586607, 35482246). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=5)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004040806.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Likely pathogenic
(Dec 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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NDUFV1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119891.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NDUFV1 c.1157G>A variant is predicted to result in the amino acid substitution p.Arg386His. This variant, along with a second potentially causative variant in NDUFV1, … (more)
The NDUFV1 c.1157G>A variant is predicted to result in the amino acid substitution p.Arg386His. This variant, along with a second potentially causative variant in NDUFV1, has been reported in two patients with mitochondrial complex I deficiency (Calvo et al. 2010. PubMed ID: 20818383, see supplementary table 2). This variant in the homozygous state has been reported in two consanguineous siblings with brainstem lesions and Leigh syndrome; both of their unaffected parents are heterozygous for this variant (Vilain et al. 2012. PubMed ID: 21696386, reported as c.1156G>A, p.Arg386His). A different variant affecting the same amino acid (p.Arg386Cys) has also been reported to be pathogenic (Srivastava et al. 2018. PubMed ID: 29976978; Breningstall et al. 2008. PubMed ID: 19073330). Functional analysis suggests that the p.Arg386His variant decreases complex I activity (Varghese et al. 2015. PubMed ID: 26345448). Taken together, we classify this variant as likely pathogenic. (less)
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Pathogenic
(May 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018243.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002247077.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 386 of the NDUFV1 protein (p.Arg386His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 386 of the NDUFV1 protein (p.Arg386His). This variant is present in population databases (rs536758576, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 20818383, 26345448, 35482246). 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: 496918). 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%. Experimental studies have shown that this missense change affects NDUFV1 function (PMID: 26345448). 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: 26024641, 29353736, 29948731). 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. (less)
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Pathogenic
(Feb 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002032668.4
First in ClinVar: Dec 18, 2021 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate a damaging effect on complex I activity (PMID: 26345448); In silico analysis supports that this missense variant has a deleterious effect … (more)
Published functional studies demonstrate a damaging effect on complex I activity (PMID: 26345448); 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: 28441825, 29976978, 24365713, 25525159, 31665838, 23562761, 27126960, Nurun2021[Article], 34740920, 35586607, 35482246, 35803560, 34807224, 26024641, 25615419, 22644603, 21364701, 28906460, 31324802, 36462614, 26345448, 21696386, 20818383) (less)
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Likely pathogenic
(Oct 07, 2024)
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criteria provided, single submitter
Method: curation
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Mitochondrial complex I deficiency, nuclear type
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001445964.2
First in ClinVar: Nov 21, 2020 Last updated: Oct 13, 2024 |
Comment:
The heterozygous p.Arg386His variant in NDUFV1 was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 … (more)
The heterozygous p.Arg386His variant in NDUFV1 was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with mitochondrial complex I deficiency, nuclear type 4. The variant has been reported in 5 individuals of Moroccan and unknown ethnicity with mitochondrial complex I deficiency (PMID: 21696386, 27126960, 20818383), segregated with disease in one affected relative from one family (PMID: 21696386). Of the 5 affected individuals, 2 siblings were homozygotes, which increases the likelihood that the p.Arg386His variant is pathogenic (PMID: 21696386). The p.Arg386His variant has been identified in In 0.03% (19/75000) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs536758576). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 496918) as pathogenic by multiple sources. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 27126960). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The variant is located in a region of NDUFV1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 29976978, 21696386, 23562761). Two additional pathogenic variants, resulting in a different amino acid change at the same position, p.Arg386Leu and p.Arg386Cys, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 1465562, 419230). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive mitochondrial complex I deficiency. ACMG/AMP Criteria applied: PP3_moderate, PM5, PM3_supporting, PM1_supporting, PS3_supporting (Richards 2015). (less)
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927835.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood. | French CE | HGG advances | 2022 | PMID: 35586607 |
Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency. | Tang X | Genes & genomics | 2022 | PMID: 35482246 |
NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms. | Zanette V | Genetics and molecular biology | 2021 | PMID: 34807224 |
Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. | Srivastava A | European journal of human genetics : EJHG | 2018 | PMID: 29976978 |
Cystic Leucoencephalopathy in NDUFV1 Mutation. | Wadhwa Y | Indian journal of pediatrics | 2018 | PMID: 29948731 |
Mitochondrial leukoencephalopathies: A border zone between acquired and inherited white matter disorders in children? | Bindu PS | Multiple sclerosis and related disorders | 2018 | PMID: 29353736 |
Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. | Varghese F | Human molecular genetics | 2015 | PMID: 26345448 |
Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency. | Leman G | The international journal of biochemistry & cell biology | 2015 | PMID: 26024641 |
Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. | Björkman K | Mitochondrion | 2015 | PMID: 25615419 |
A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations. | Ortega-Recalde O | Mitochondrion | 2013 | PMID: 23562761 |
A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. | Vilain C | Clinical genetics | 2012 | PMID: 21696386 |
Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. | Swalwell H | European journal of human genetics : EJHG | 2011 | PMID: 21364701 |
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NDUFV1 | - | - | - | - |
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Text-mined citations for rs536758576 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.