ClinVar Genomic variation as it relates to human health
NM_000135.4(FANCA):c.3391A>G (p.Thr1131Ala)
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.3391A>G (p.Thr1131Ala)
Variation ID: 237048 Accession: VCV000237048.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89746848 (GRCh38) [ NCBI UCSC ] 16: 89813256 (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 Aug 20, 2017 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000135.4:c.3391A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000126.2:p.Thr1131Ala missense NM_000135.3:c.3391A>G NM_001286167.3:c.3391A>G NP_001273096.1:p.Thr1131Ala missense NC_000016.10:g.89746848T>C NC_000016.9:g.89813256T>C NG_011706.1:g.74810A>G LRG_495:g.74810A>G LRG_495t1:c.3391A>G O15360:p.Thr1131Ala - Protein change
- T1131A
- Other names
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- Canonical SPDI
- NC_000016.10:89746847:T:C
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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) 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
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
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 | |
LOC132090450 | - | - | - | GRCh38 | - | 91 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000230300.13 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV000498721.29 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 26, 2022 | RCV000665186.16 |
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
(Aug 03, 2016)
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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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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448867.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481589.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 9371798, 26556299, 27577878, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 9371798, 26556299, 27577878, 25525159, ClinVar ID: 237048] (less)
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Pathogenic
(Jul 26, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715181.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4, PM1, PM2,
Number of individuals with the variant: 1
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Likely pathogenic
(May 06, 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: SCV002067478.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.3391A>G, in exon 34 that results in an amino acid change, p.Thr1131Ala. This sequence … (more)
DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.3391A>G, in exon 34 that results in an amino acid change, p.Thr1131Ala. This sequence change has been previously described in several patients with a clinical diagnosis of Fanconi anemia (PMIDs: 19278965, 9371798, 15643609); in some patients in a biallelic state with multi-exonic deletions (PMIDs: 17924555, 19367192) and in one patient in a homozygous state (PMID: 22778927). Some experimental studies showed that the mutant protein behaved similar to wild type-FANCA with respect to its interaction with FANCC, phosphorylation and localization to the nuclei (PMID: 12444097); however, authors proposed that further studies analyzing its mRNA and protein expression are required. The p.Thr1131Ala change affects a highly conserved amino acid residue located in a domain of the FANCA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr1131Ala substitution. This sequence change has been described in the gnomAD database with a low population frequency of 0.0083% (dbSNP rs574034197). These collective evidences indicate that this sequence change is likely pathogenic. (less)
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Pathogenic
(Nov 05, 2021)
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criteria provided, single submitter
Method: curation
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535001.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The FANCA c.3391A>G (p.T1131A) has been reported as compound heterozygous or as homozygous in numerous individuals with Fanconi anemia (PMID: 27577878, 29098742, 22778927, among others). … (more)
The FANCA c.3391A>G (p.T1131A) has been reported as compound heterozygous or as homozygous in numerous individuals with Fanconi anemia (PMID: 27577878, 29098742, 22778927, among others). One functional study demonstrated MMC hypersensitivity, protein localization, phosphorylation, interaction with other FANC complex subunits, and FANCD2 ubiquitination comparable to wild type (PMID: 12444097). Another demonstrated that this variant resulted in significantly decreased FANCD2 monoubiquitination and decreased quantity of FANCD2 foci before and after mitomyocin C treatment (PMID: 28864460). It was observed in 12/85380 chromosomes of the Non-Finnish European subpopulation, with 0 homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 237048). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 01, 2021)
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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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Myriad Genetics, Inc.
Accession: SCV002060324.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000135.2(FANCA):c.3391A>G(T1131A) is a missense variant classified as pathogenic in the context of Fanconi anemia complementation group A. T1131A has been observed in cases with relevant … (more)
NM_000135.2(FANCA):c.3391A>G(T1131A) is a missense variant classified as pathogenic in the context of Fanconi anemia complementation group A. T1131A has been observed in cases with relevant disease (PMID: 22778927, 19367192, 15643609, 19278965, 19367192). Functional assessments of this variant are available in the literature (PMID: 12444097). T1131A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000135.2(FANCA):c.3391A>G(T1131A) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Dec 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: SCV000589393.3
First in ClinVar: Aug 20, 2017 Last updated: Dec 17, 2022 |
Comment:
Published functional studies demonstrate that the p.(T1131A) variant significantly decreases FANCD2 monoubiquitination (Wilkes et al., 2017); In silico analysis supports that this missense variant has … (more)
Published functional studies demonstrate that the p.(T1131A) variant significantly decreases FANCD2 monoubiquitination (Wilkes et al., 2017); 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: 25525159, 1792455, 27577878, 12444097, 9371798, 19367192, 15643609, 17924555, 26556299, 22778927, 31192125, 33332384, 29641532, 28864460, 29098742) (less)
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Pathogenic
(May 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: SCV000894100.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004218556.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00014 (12/85380 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been … (more)
The frequency of this variant in the general population, 0.00014 (12/85380 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Fanconi anemia (FA) (PMIDs: 31192125 (2019), 29098742 (2018), 27577878 (2017), 22778927 (2012), 19367192 (2009), 17924555 (2008), 15643609 (2005)) and has been described affected individuals in the homozygous state as well as in trans with another pathogenic FANCA variant. One functional study suggests that this variant has similar properties as the wild-type in regards to phosphorylation and interaction with FANCC, but additional functional studies are needed to conclude this variant’s overall impact on gene and gene product (PMID: 12444097 (2002)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 12, 2019)
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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:
germline
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Revvity Omics, Revvity
Accession: SCV002022312.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 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: SCV000283560.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1131 of the FANCA protein (p.Thr1131Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1131 of the FANCA protein (p.Thr1131Ala). This variant is present in population databases (rs574034197, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 1792455, 1927896, 9371798, 12444097, 15643609, 19367192, 22778927). 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: 237048). 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 FANCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect FANCA function (PMID: 12444097). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 2023)
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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: SCV001501640.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
FANCA: PM3:Strong, PM2
Number of individuals with the variant: 4
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Pathogenic
(Feb 28, 2020)
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no assertion criteria provided
Method: curation
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Fanconi anemia complementation group A
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001425707.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Sue Richards.
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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: SCV001462879.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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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Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia. | Engel NW | Frontiers in oncology | 2019 | PMID: 31192125 |
A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families. | Kimble DC | Human mutation | 2018 | PMID: 29098742 |
A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents. | Wilkes DC | Cold Spring Harbor molecular case studies | 2017 | PMID: 28864460 |
Maintenance of genome stability by Fanconi anemia proteins. | Palovcak A | Cell & bioscience | 2017 | PMID: 28239445 |
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
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 |
Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing. | Gille JJ | Anemia | 2012 | PMID: 22778927 |
Validation of Fanconi anemia complementation Group A assignment using molecular analysis. | Moghrabi NN | Genetics in medicine : official journal of the American College of Medical Genetics | 2009 | PMID: 19367192 |
Diagnosis of Fanconi anemia in patients with bone marrow failure. | Pinto FO | Haematologica | 2009 | PMID: 19278965 |
Genetic subtyping of Fanconi anemia by comprehensive mutation screening. | Ameziane N | Human mutation | 2008 | PMID: 17924555 |
Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study. | Levran O | Human mutation | 2005 | PMID: 15643609 |
Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants. | Adachi D | Human molecular genetics | 2002 | PMID: 12444097 |
Sequence variation in the Fanconi anemia gene FAA. | Levran O | Proceedings of the National Academy of Sciences of the United States of America | 1997 | PMID: 9371798 |
On FDA's future. | Samuel FE Jr | American pharmacy | 1991 | PMID: 1927896 |
Leucocyte count as an alternative to ESR in general practice? | Dinant GJ | Scandinavian journal of primary health care | 1991 | PMID: 1792455 |
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Text-mined citations for rs574034197 ...
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.