ClinVar Genomic variation as it relates to human health
NM_000135.4(FANCA):c.2852G>A (p.Arg951Gln)
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_000135.4(FANCA):c.2852G>A (p.Arg951Gln)
Variation ID: 526433 Accession: VCV000526433.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89761949 (GRCh38) [ NCBI UCSC ] 16: 89828357 (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 May 28, 2018 May 12, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000135.4:c.2852G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000126.2:p.Arg951Gln missense NM_001286167.3:c.2852G>A NP_001273096.1:p.Arg951Gln missense NC_000016.10:g.89761949C>T NC_000016.9:g.89828357C>T NG_011706.1:g.59709G>A LRG_495:g.59709G>A LRG_495t1:c.2852G>A - Protein change
- R951Q
- Other names
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- Canonical SPDI
- NC_000016.10:89761948: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00013
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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FANCA | - | - |
GRCh38 GRCh37 |
4075 | 5201 |
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 (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000630961.9 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000666705.8 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 8, 2022 | RCV001569733.26 |
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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Likely pathogenic
(Apr 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791048.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Feb 14, 2020)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002070494.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
The sequence change, c.2852G>A, in exon 29 results in an amino acid change, p.Arg951Gln. This sequence change has been described in the gnomAD database with … (more)
The sequence change, c.2852G>A, in exon 29 results in an amino acid change, p.Arg951Gln. This sequence change has been described in the gnomAD database with a low population frequency of 0.01% in European sub-population (dbSNP rs755922289). The p.Arg951Gln change affects a highly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg951Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Arg951Gln change has been reported in several individuals with Fanconi anemia (PMID: 17924555, 22778927, 24584348). In one of these individuals, this sequence change was shown to be in trans with a different pathogenic sequence change (PMID: 24584348). A different pathogenic sequence change affecting the same amino acid residue, p.Arg951Trp, has also been described in patients with FANCA-related disorders (PMID: 22778927, 17924555, 24584348, 26799702, 17924555, 24584348, 24349332). Functional studies have demonstrated disrupted protein function in the presence of the p.Arg951Gln change (PMID: 12697994). These collective evidences indicate that this sequence change is likely pathogenic. (less)
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Pathogenic
(Apr 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804623.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 08, 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: SCV001793868.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: retention in the cytoplasm preventing cells from repairing DNA (Bottega et al,. 2018); In silico analysis supports that … (more)
Published functional studies demonstrate a damaging effect: retention in the cytoplasm preventing cells from repairing DNA (Bottega et al,. 2018); 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: 24584348, 28102861, 25525159, 17924555, 12697994, 11063725, 22778927, 32054657, 28973083, 29269525) (less)
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195995.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000751937.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 951 of the FANCA protein (p.Arg951Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 951 of the FANCA protein (p.Arg951Gln). This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. This variant is present in population databases (rs755922289, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 17924555, 22778927, 24584348). 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: 526433). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects FANCA function (PMID: 12697994). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts the p.Arg951 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924555, 22778927, 24349332, 24584348, 26799702). 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
(Sep 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961640.15
First in ClinVar: Oct 08, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia, group A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001452857.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely 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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809681.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 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: SCV001959168.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001737414.2
First in ClinVar: Jun 19, 2021 Last updated: Oct 01, 2022 |
Comment:
Associated with slower hematologic disease progression
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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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Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia. | Bottega R | Haematologica | 2018 | PMID: 29269525 |
FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients. | Solanki A | PloS one | 2016 | PMID: 26799702 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology. | De Rocco D | Haematologica | 2014 | PMID: 24584348 |
Human Fanconi anemia complementation group a protein stimulates the 5' flap endonuclease activity of FEN1. | Qian L | PloS one | 2013 | PMID: 24349332 |
Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing. | Gille JJ | Anemia | 2012 | PMID: 22778927 |
Genetic subtyping of Fanconi anemia by comprehensive mutation screening. | Ameziane N | Human mutation | 2008 | PMID: 17924555 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction. | Gross M | Cytogenetic and genome research | 2002 | PMID: 12697994 |
The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. | de Winter JP | Human molecular genetics | 2000 | PMID: 11063725 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs755922289 ...
HelpRecord last updated May 12, 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.