ClinVar Genomic variation as it relates to human health
NM_005262.3(GFER):c.581G>A (p.Arg194His)
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_005262.3(GFER):c.581G>A (p.Arg194His)
Variation ID: 8691 Accession: VCV000008691.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 1985991 (GRCh38) [ NCBI UCSC ] 16: 2035992 (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 31, 2013 Feb 14, 2024 Dec 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005262.3:c.581G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005253.3:p.Arg194His missense NC_000016.10:g.1985991G>A NC_000016.9:g.2035992G>A NG_016288.1:g.6843G>A P55789:p.Arg194His - Protein change
- R194H
- Other names
- p.R194H:CGC>CAC
- Canonical SPDI
- NC_000016.10:1985990: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
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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GFER | - | - |
GRCh38 GRCh38 GRCh37 |
91 | 208 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Oct 10, 2022 | RCV000009228.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2022 | RCV000199876.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2017 | RCV000624237.2 |
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
Help
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
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760361.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000807608.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 13-year-old male … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 13-year-old male with profound delays, tremulousness, respiratory distress, congenital ataracts, hypoglycemia, lactic acidemia, autistic features, scoliosis, pica, hypotonia, intermittent alopecia, osteoporosis, episodes of hypophosphatemia. Similarly affected sister had same compound heterozygous genotype. Heterozygotes are expected to be asymptomatic carriers. (less)
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Pathogenic
(Feb 04, 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: SCV000251537.13
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect (protein instability and altered localization) (Daithankar et al., 2010; Di Fonzo et al., 2009); Not observed at significant … (more)
Published functional studies suggest a damaging effect (protein instability and altered localization) (Daithankar et al., 2010; Di Fonzo et al., 2009); 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: 25269795, 26018198, 33144682, 19409522, 26944241, 20593814, 28155230) (less)
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Pathogenic
(Jul 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742501.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818168.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 24, 2022)
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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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Invitae
Accession: SCV003292684.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GFER function (PMID: 19409522, 25269795). Algorithms … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GFER function (PMID: 19409522, 25269795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 8691). This missense change has been observed in individuals with mitochondrial myopathy (PMID: 19409522, 26018198, 26944241). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908192, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 194 of the GFER protein (p.Arg194His). (less)
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Pathogenic
(Mar 08, 2016)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802112.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Dec 15, 2014)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MITOCHONDRIAL PROGRESSIVE, WITH CONGENITAL CATARACT AND DEVELOPMENTAL DELAY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029446.6
First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2021 |
Comment on evidence:
In 3 children born to consanguineous Moroccan parents with a progressive mitochondrial myopathy and combined respiratory chain deficiency (MPMCD; 613076), Di Fonzo et al. (2009) … (more)
In 3 children born to consanguineous Moroccan parents with a progressive mitochondrial myopathy and combined respiratory chain deficiency (MPMCD; 613076), Di Fonzo et al. (2009) identified a homozygous G-to-A transition at nucleotide 581 in exon 3 of the GFER gene, resulting in an arg-to-his substitution at codon 194 (R194H). This mutation was not identified in 380 samples from unrelated European individuals and 183 samples from unrelated Arab individuals, including 156 Moroccans. Confocal microscopy and immunoblot analysis showed that R194H mutant GFER is less stable than wildtype protein within the mitochondria. By next-generation sequencing of a nuclear gene panel for mitochondrial disease, Calderwood et al. (2016) identified a patient with MPMCD who was compound heterozygous for mutations in the GFER gene: R194H and a c.373C-T transition, resulting in a gln125-to-ter substitution (Q125X; 600294.0002). This patient also had adrenal insufficiency and had previously been reported by North et al. (1996). In 2 sibs (patients 3 and 4) with MPMCD, Nambot et al. (2017) identified compound heterozygous mutations in the GFER gene: R194H and a 1-bp deletion in exon 1 (c.217delG; 600924.0005), resulting in a frameshift and a premature stop codon (600924.0005). Each parent was heterozygous for one of the mutations. Neither variant was present in the ExAC database. Variant Function Ceh-Pavia et al. (2014) characterized recombinant yeast Erv1 containing an R182H mutation, which corresponds to the R194H mutation in the human ortholog. The mutation did not affect the FAD content of Erv1, but it disturbed the secondary, tertiary, and quaternary structures of Erv1, with the mutant protein forming a dimer instead of a tetramer like wildtype. The Erv1 R182H mutant had both decreased thermal stability and weaker FAD-binding compared with wildtype. The mutation not only caused a defect in Erv1 shuttling of electrons to molecular oxygen, but also in the ability of Erv1 to reduce cytochrome c. The gradual inactivation of Erv1 resulted from loss of cofactor during the catalytic reaction, and this functional defect could be rescued with the addition of extra FAD or excessive Erv1 in vitro. Likewise, the growth defect of the Erv1 R182H mutant yeast strain could be rescued by increasing the concentration of the mutant protein through overexpression in vivo. By structural and other analyses of human ALR, Daithankar et al. (2010) found that the R194H mutation had a large effect on protein stability and flavin binding, but that it did not impact enzyme activity and other biophysical features of ALR. (less)
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not provided
(-)
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no classification provided
Method: not provided
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Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091145.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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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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Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data. | Nambot S | Clinical genetics | 2017 | PMID: 28155230 |
Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience. | Lazaridis KN | Mayo Clinic proceedings | 2016 | PMID: 26944241 |
Adrenal Insufficiency in Mitochondrial Disease: A Rare Case of GFER-Related Mitochondrial Encephalomyopathy and Review of the Literature. | Calderwood L | Journal of child neurology | 2016 | PMID: 26018198 |
The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. | Di Fonzo A | American journal of human genetics | 2009 | PMID: 19409522 |
Oxidative phosphorylation defect associated with primary adrenal insufficiency. | North K | The Journal of pediatrics | 1996 | PMID: 8627443 |
Text-mined citations for rs121908192 ...
HelpRecord last updated Mar 17, 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.