ClinVar Genomic variation as it relates to human health
NM_024996.7(GFM1):c.2011C>T (p.Arg671Cys)
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
-
NM_024996.7(GFM1):c.2011C>T (p.Arg671Cys)
Variation ID: 214500 Accession: VCV000214500.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q25.32 3: 158690264 (GRCh38) [ NCBI UCSC ] 3: 158408053 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 Feb 14, 2024 Dec 10, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_024996.7:c.2011C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079272.4:p.Arg671Cys missense NM_001308164.2:c.2068C>T NP_001295093.1:p.Arg690Cys missense NM_001374355.1:c.1930C>T NP_001361284.1:p.Arg644Cys missense NM_001374356.1:c.1894C>T NP_001361285.1:p.Arg632Cys missense NM_001374357.1:c.1786C>T NP_001361286.1:p.Arg596Cys missense NM_001374358.1:c.1552C>T NP_001361287.1:p.Arg518Cys missense NM_001374359.1:c.1444C>T NP_001361288.1:p.Arg482Cys missense NM_001374360.1:c.1444C>T NP_001361289.1:p.Arg482Cys missense NM_001374361.1:c.1327C>T NP_001361290.1:p.Arg443Cys missense NR_164499.1:n.2034C>T non-coding transcript variant NR_164500.1:n.1974C>T non-coding transcript variant NR_164501.1:n.1519C>T non-coding transcript variant NR_164502.1:n.1998C>T non-coding transcript variant NC_000003.12:g.158690264C>T NC_000003.11:g.158408053C>T NG_008441.1:g.50737C>T - Protein change
- R671C, R690C, R443C, R482C, R518C, R596C, R632C, R644C
- Other names
- p.R671C:CGC>TGC
- Canonical SPDI
- NC_000003.12:158690263:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
GFM1 | - | - |
GRCh38 GRCh37 |
849 | 896 |
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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 10, 2023 | RCV000197077.9 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2023 | RCV000763507.11 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894303.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation deficiency 1
Affected status: yes
Allele origin:
inherited
|
Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades
Accession: SCV001160692.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Number of individuals with the variant: 6
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kids Research, The Children's Hospital at Westmead
Accession: SCV001244724.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
Pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000251564.13
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
Comment:
Published functional studies demonstrate oxidative phosphorylation dysfunction in liver mitochondria (Molina-Berenguer et al., 2022); In silico analysis supports that this missense variant has a deleterious … (more)
Published functional studies demonstrate oxidative phosphorylation dysfunction in liver mitochondria (Molina-Berenguer et al., 2022); 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: 27345796, 21986555, 22277967, 25852744, 26937387, 32313153, 31680380, 34919756, 34440436, 35581596) (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047783.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense c.2011C>T(p.Arg671Cys) variant in GFM1 gene has been reported previously in the homozygous and compound heterozygous state in patients with complex IV deficiency (Galmiche … (more)
The missense c.2011C>T(p.Arg671Cys) variant in GFM1 gene has been reported previously in the homozygous and compound heterozygous state in patients with complex IV deficiency (Galmiche et al., 2012; Calvo et al., 2012). This variant is reported with the allele frequency 0.006% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Arg at position 671 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg671Cys in GFM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, the variant has been classified as Likely pathogenic. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present)
|
|
Pathogenic
(Sep 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199302.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jun 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024241.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001236979.5
First in ClinVar: Apr 15, 2020 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 671 of the GFM1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the GFM1 protein (p.Arg671Cys). This variant is present in population databases (rs201408725, gnomAD 0.03%). This missense change has been observed in individual(s) with oxidative phosphorylation deficiency (PMID: 21986555, 22277967, 25852744, 31680380). 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: 214500). 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 GFM1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease. | Riley LG | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32313153 |
Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations. | Barcia G | Human mutation | 2020 | PMID: 31680380 |
Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and GFM1 mutations. | Brito S | Frontiers in genetics | 2015 | PMID: 25852744 |
Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. | Calvo SE | Science translational medicine | 2012 | PMID: 22277967 |
Toward genotype phenotype correlations in GFM1 mutations. | Galmiche L | Mitochondrion | 2012 | PMID: 21986555 |
Text-mined citations for rs201408725 ...
HelpRecord last updated Apr 06, 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.