ClinVar Genomic variation as it relates to human health
NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)
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.1156C>T (p.Arg386Cys)
Variation ID: 419230 Accession: VCV000419230.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 67611972 (GRCh38) [ NCBI UCSC ] 11: 67379443 (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 27, 2017 Sep 16, 2024 Aug 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007103.4:c.1156C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009034.2:p.Arg386Cys missense NM_001166102.2:c.1129C>T NP_001159574.1:p.Arg377Cys missense NC_000011.10:g.67611972C>T NC_000011.9:g.67379443C>T NG_013353.1:g.10121C>T - Protein change
- R386C, R377C
- Other names
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- Canonical SPDI
- NC_000011.10:67611971:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00012
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
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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 |
351 | 501 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 8, 2024 | RCV000482108.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2018 | RCV001004858.2 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 18, 2023 | RCV001662464.10 |
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
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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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Likely pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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Mitochondrial complex I deficiency, nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164336.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
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 … (more)
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). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Mitochondrial complex 1 deficiency, nuclear type 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Bruce Lefroy Centre, Murdoch Childrens Research Institute
Accession: SCV001879330.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001976533.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Sex: male
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Pathogenic
(Jan 09, 2024)
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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: SCV002133943.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 08, 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: SCV000566902.5
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
Has been reported previously in individuals with mitochondrial complex I deficiency who were homozygous for R386C, or were compound heterozygous R386C with another NDUFV1 variant, … (more)
Has been reported previously in individuals with mitochondrial complex I deficiency who were homozygous for R386C, or were compound heterozygous R386C with another NDUFV1 variant, in published literature and patients referred for genetic testing at GeneDx (PMID: 23562761, 19073330, 26684010); Published functional studies demonstrate a damaging effect: the R386C variant results in an impaired complex I activity with decreased flavin mononucleotide (FMN) content (PMID: 26345448); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26684010, 27126960, 28441825, 33182419, 23266820, 19073330, 23562761, 26024641, 29272804, 29353736, 29948731, 30777920, 29976978, 32180488, 32005694, 34302356, 35803560, 36801247, 26345448) (less)
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768369.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820278.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Global developmental delay (present)
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Pathogenic
(Oct 18, 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: SCV003825896.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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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Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL. | Borna NN | Genes | 2020 | PMID: 33182419 |
Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel. | Parayil Sankaran B | Journal of child neurology | 2020 | PMID: 32180488 |
Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. | Srivastava A | European journal of human genetics : EJHG | 2018 | PMID: 29976978 |
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 |
A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations. | Ortega-Recalde O | Mitochondrion | 2013 | PMID: 23562761 |
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
Siblings with leukoencephalopathy. | Breningstall GN | Seminars in pediatric neurology | 2008 | PMID: 19073330 |
Text-mined citations for rs150966634 ...
HelpRecord last updated Sep 29, 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.