The p.W22* pathogenic mutation (also known as c.65G>A), located in coding exon 1 of the FANCC gene, results from a G to A substitution at nucleotide position 65. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration has been identified in the homozygous state in several patients with Fanconi Anemia (Gibson RA et al. Hum Mutat. 1996;8:140-8; Ameziane N et al. Hum Mutat. 2008 Jan;29:159-66; Pilonetto DV et al. Mol Genet Genomic Med. 2017 Jul;5:360-372). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ClinVar Genomic variation as it relates to human health
NM_000136.3(FANCC):c.65G>A (p.Trp22Ter)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000136.3(FANCC):c.65G>A (p.Trp22Ter)
Variation ID: 188926 Accession: VCV000188926.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q22.32 9: 95249227 (GRCh38) [ NCBI UCSC ] 9: 98011509 (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 Mar 29, 2015 Sep 29, 2024 Dec 26, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000136.3:c.65G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000127.2:p.Trp22Ter nonsense NM_001243743.2:c.65G>A NP_001230672.1:p.Trp22Ter nonsense NM_001243744.2:c.65G>A NP_001230673.1:p.Trp22Ter nonsense NC_000009.12:g.95249227C>T NC_000009.11:g.98011509C>T NG_011707.1:g.73483G>A LRG_497:g.73483G>A LRG_497t1:c.65G>A - Protein change
- W22*
- Other names
- -
- Canonical SPDI
- NC_000009.12:95249226: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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. |
|||
| FANCC | - | - |
GRCh38 GRCh37 |
659 | 2019 | |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV000169293.8 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 26, 2023 | RCV001390247.7 | |
|
FANCC-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2023 | RCV003407628.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2021 | RCV002362865.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 25, 2023 | RCV004719732.1 |
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
(Jun 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002663424.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W22* pathogenic mutation (also known as c.65G>A), located in coding exon 1 of the FANCC gene, results from a G to A substitution at … (more)
The p.W22* pathogenic mutation (also known as c.65G>A), located in coding exon 1 of the FANCC gene, results from a G to A substitution at nucleotide position 65. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration has been identified in the homozygous state in several patients with Fanconi Anemia (Gibson RA et al. Hum Mutat. 1996;8:140-8; Ameziane N et al. Hum Mutat. 2008 Jan;29:159-66; Pilonetto DV et al. Mol Genet Genomic Med. 2017 Jul;5:360-372). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695435.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Comment:
Variant summary: The FANCC c.65G>A (p.Trp22X) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense … (more)
Variant summary: The FANCC c.65G>A (p.Trp22X) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.67delG/p.Asp23fsX23, c.1642C>T/p.Arg548X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121148 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). This variant has been reported in at least three patients with Fanconi Anemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591920.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCC gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs377294947, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 8844212, 28717661). ClinVar contains an entry for this variant (Variation ID: 188926). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163260.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
FANCC-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004106264.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FANCC c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported in the homozygous state in at least … (more)
The FANCC c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported in the homozygous state in at least two patients with Fanconi anaemia (Gibson et al. 1996. PubMed ID: 8844212; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98011509-C-T). Nonsense variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894485.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Likely pathogenic
(Aug 20, 2014)
|
criteria provided, single submitter
Method: literature only
|
Fanconi anemia, complementation group C
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220611.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325764.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34774576, 29922827, 17924555, 12670332, 28717661, 8844212, 27832981, Rodriguez2005[article]) (less)
|
|
|
Pathogenic
(Feb 28, 2020)
|
no assertion criteria provided
Method: curation
|
Fanconi anemia complementation group C
Affected status: yes
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001365307.1
First in ClinVar: Jun 29, 2020 Last updated: Jun 29, 2020 |
Comment:
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Fanconi anemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081314.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Variant summary: The FANCC c.65G>A (p.Trp22X) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.67delG/p.Asp23fsX23, c.1642C>T/p.Arg548X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121148 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). This variant has been reported in at least three patients with Fanconi Anemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs377294947, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 8844212, 28717661). ClinVar contains an entry for this variant (Variation ID: 188926). For these reasons, this variant has been classified as Pathogenic.
Comment:
The FANCC c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported in the homozygous state in at least two patients with Fanconi anaemia (Gibson et al. 1996. PubMed ID: 8844212; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98011509-C-T). Nonsense variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34774576, 29922827, 17924555, 12670332, 28717661, 8844212, 27832981, Rodriguez2005[article])
Comment:
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.
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. |
Comment:
The p.W22* pathogenic mutation (also known as c.65G>A), located in coding exon 1 of the FANCC gene, results from a G to A substitution at nucleotide position 65. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration has been identified in the homozygous state in several patients with Fanconi Anemia (Gibson RA et al. Hum Mutat. 1996;8:140-8; Ameziane N et al. Hum Mutat. 2008 Jan;29:159-66; Pilonetto DV et al. Mol Genet Genomic Med. 2017 Jul;5:360-372). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant summary: The FANCC c.65G>A (p.Trp22X) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.67delG/p.Asp23fsX23, c.1642C>T/p.Arg548X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121148 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). This variant has been reported in at least three patients with Fanconi Anemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs377294947, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 8844212, 28717661). ClinVar contains an entry for this variant (Variation ID: 188926). For these reasons, this variant has been classified as Pathogenic.
Comment:
The FANCC c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported in the homozygous state in at least two patients with Fanconi anaemia (Gibson et al. 1996. PubMed ID: 8844212; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98011509-C-T). Nonsense variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34774576, 29922827, 17924555, 12670332, 28717661, 8844212, 27832981, Rodriguez2005[article])
Comment:
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A strategy for molecular diagnostics of Fanconi anemia in Brazilian patients. | Pilonetto DV | Molecular genetics & genomic medicine | 2017 | PMID: 28717661 |
| Genetic subtyping of Fanconi anemia by comprehensive mutation screening. | Ameziane N | Human mutation | 2008 | PMID: 17924555 |
| Novel mutations and polymorphisms in the Fanconi anemia group C gene. | Gibson RA | Human mutation | 1996 | PMID: 8844212 |
Text-mined citations for rs377294947 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.