ClinVar Genomic variation as it relates to human health
NM_001002755.4(NFU1):c.622G>T (p.Gly208Cys)
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_001002755.4(NFU1):c.622G>T (p.Gly208Cys)
Variation ID: 30700 Accession: VCV000030700.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.3 2: 69400462 (GRCh38) [ NCBI UCSC ] 2: 69627594 (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 Oct 23, 2016 Feb 14, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001002755.4:c.622G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001002755.1:p.Gly208Cys missense NM_001002756.2:c.199G>T NP_001002756.1:p.Gly67Cys missense NM_001374284.1:c.550G>T NP_001361213.1:p.Gly184Cys missense NM_015700.4:c.550G>T NP_056515.2:p.Gly184Cys missense NR_045631.2:n.499G>T non-coding transcript variant NC_000002.12:g.69400462C>A NC_000002.11:g.69627594C>A NG_031931.1:g.42167G>T Q9UMS0:p.Gly208Cys - Protein change
- G208C, G67C, G184C
- Other names
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- Canonical SPDI
- NC_000002.12:69400461:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00017
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
Help
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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NFU1 | - | - |
GRCh38 GRCh37 |
148 | 182 |
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
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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV000023678.14 | |
Pathogenic (3) |
criteria provided, single submitter
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Feb 16, 2022 | RCV000385109.8 | |
NFU1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2023 | RCV003415735.4 |
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
Help
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
(May 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984858.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant has been previously reported as a compound heterozygous and homozygous change in patients with mitochondrial disease and cystic leukoencephalopathy (PMID: 22077971, 24462778, 28803783, … (more)
This variant has been previously reported as a compound heterozygous and homozygous change in patients with mitochondrial disease and cystic leukoencephalopathy (PMID: 22077971, 24462778, 28803783, 29441221). Functional studies showed absence of protein-bound lipoic acid in fibroblasts from individuals with this variant in the homozygous and compound heterozygous state, and decreased levels of lipoic acid in muscle biopsies from these individuals (PMID: 22077971, 23179554). It is present in the heterozygous state in the gnomAD population database at a frequency of .013% (38/282860) and thus is presumed to be rare. The c.622G>T (p.Gly208Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.622G>T (p.Gly208Cys) variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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NFU1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115995.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NFU1 c.622G>T variant is predicted to result in the amino acid substitution p.Gly208Cys. This variant has been reported in the homozygous and compound heterozygous … (more)
The NFU1 c.622G>T variant is predicted to result in the amino acid substitution p.Gly208Cys. This variant has been reported in the homozygous and compound heterozygous states in patients with multiple mitochondrial dysfunctions syndrome 1 (Navarro-Sastre et al. 2011. PubMed ID: 22077971; Lebigot et al. 2017. PubMed ID: 28803783). In vitro functional studies suggest that this variant impairs the transfer of Fe-S clusters to target apoproteins, and causes defects in the lipoic acid biosynthesis and complex II pathways (Ferrer-Cortès et al. 2013. PubMed ID: 23179554; Lebigot et al. 2017. PubMed ID: 28803783; Wachnowsky et al. 2017. PubMed ID: 28161430). This variant is reported in 0.085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-69627594-C-A). This variant is interpreted as pathogenic. (less)
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Pathogenic
(May 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018329.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002243592.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 208 of the NFU1 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 208 of the NFU1 protein (p.Gly208Cys). This variant is present in population databases (rs374514431, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of multiple mitochondrial dysfunctions syndrome (PMID: 22077971, 28803783, 29441221, 31970900). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30700). 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 NFU1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NFU1 function (PMID: 22077971, 28161430, 31461310). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 16, 2022)
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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: SCV000329903.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
In vitro functional studies in yeast showed that NFU1 protein with the G208C variant is functionally impaired (Navarro-Sastre et al., 2011), and protein expression profiles … (more)
In vitro functional studies in yeast showed that NFU1 protein with the G208C variant is functionally impaired (Navarro-Sastre et al., 2011), and protein expression profiles were impaired in fibroblasts from patients who are homozygous or compound heterozygous for the G208C variant (Ferrer-Corts et al., 2013).; 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: 28161430, 24462778, 23179554, 22077971, 28803783, 29019354, 28906593, 25918518, 29441221, 31970900, 31589614) (less)
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Pathogenic
(Jan 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple mitochondrial dysfunctions syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520895.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023 |
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Pathogenic
(Nov 11, 2011)
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no assertion criteria provided
Method: literature only
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MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044969.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In 9 patients from unrelated Spanish families with fatal multiple mitochondrial dysfunctions syndrome-1 (MMDS1; 605711), Navarro-Sastre et al. (2011) identified a homozygous 622G-T transversion in … (more)
In 9 patients from unrelated Spanish families with fatal multiple mitochondrial dysfunctions syndrome-1 (MMDS1; 605711), Navarro-Sastre et al. (2011) identified a homozygous 622G-T transversion in exon 7 of the NFU1 gene, resulting in a gly208-to-cys (G208C) substitution in a highly conserved residue close to the Fe-S cluster binding motif. The mutation was not found in 220 controls. A tenth Spanish patient was compound heterozygous for G208C and 545G-A (608100.0001). Four of the families were of Basque origin, suggesting a founder effect. The patients presented between 1 and 9 months of age with failure to thrive, neurologic regression, or pulmonary hypertension. All died by age 15 months. Biochemical findings included increased lactate and glycine, increased urinary 2-ketoacids, and impaired oxidation. Patient fibroblasts showed decreased activity of the pyruvate dehydrogenase (PDH) complex and liver tissue showed low activity of the glycine decarboxylase system (238300). Muscle homogenates from patients showed evidence of defective lipoylation and impaired synthesis of lipoic acid, with decreased levels of PDH- and alpha-ketoglutarate dehydrogenase (AKGDH; 613022)-bound lipoic acid. NFU1 protein levels were normal. The findings indicated that proper NFU1 activity is required for lipoic acid synthetase (LIAS; 607031) activity. Depletion of NFU1 in HeLa cells showed decreased levels of lipoic acid bound to E2 subunits of the PDH complex and AKGDH, and decreased levels and activity of succinate dehydrogenase (SDH; mitochondrial complex II; 185470). In contrast to ISCU (611911), which plays a scaffolding role, NFU1 appears to play a specific, auxiliary role late in the biogenesis of SDH and LIAS, 2 Fe-S apoproteins. Transfection of the homologous G208C mutation in yeast showed that it was functionally impaired. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799874.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957563.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension. | Birjiniuk A | American journal of medical genetics. Part A | 2020 | PMID: 31970900 |
Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension. | Niihori M | American journal of respiratory cell and molecular biology | 2020 | PMID: 31461310 |
NFU1 -Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy. | de Souza PVS | Journal of pediatric genetics | 2018 | PMID: 29441221 |
Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients. | Lebigot E | Molecular genetics and metabolism | 2017 | PMID: 28803783 |
Understanding the Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1)-Impact of a Disease-Causing Gly208Cys Substitution on Structure and Activity of NFU1 in the Fe/S Cluster Biosynthetic Pathway. | Wachnowsky C | Journal of molecular biology | 2017 | PMID: 28161430 |
A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. | Navarro-Sastre A | American journal of human genetics | 2011 | PMID: 22077971 |
Text-mined citations for rs374514431 ...
HelpRecord last updated May 19, 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.