VCV000552738.43 - ClinVar

NM_000135.4(FANCA):c.856C>T (p.Gln286Ter)

Germline

Classification

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.

(9)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000135.4(FANCA):c.856C>T (p.Gln286Ter)

Variation ID: 552738 Accession: VCV000552738.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89799203 (GRCh38) [ NCBI UCSC ] 16: 89865611 (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	Aug 5, 2018	Oct 20, 2024	Aug 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.856C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000126.2:p.Gln286Ter	nonsense
NM_001018112.3:c.856C>T	NP_001018122.1:p.Gln286Ter	nonsense
NM_001286167.3:c.856C>T	NP_001273096.1:p.Gln286Ter	nonsense
NM_001351830.2:c.760C>T	NP_001338759.1:p.Gln254Ter	nonsense
NC_000016.10:g.89799203G>A
NC_000016.9:g.89865611G>A
NG_011706.1:g.22455C>T
LRG_495:g.22455C>T
LRG_495t1:c.856C>T

... more HGVS ... less HGVS

Protein change

Q286*, Q254*

Other names

Canonical SPDI

NC_000016.10:89799202:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1291524243 VarSome

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
Gene	OMIM	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.
FANCA		-	-	GRCh38 GRCh37	4167	5325

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.
Fanconi anemia complementation group A	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 21, 2022	RCV000668057.12
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 3, 2021	RCV001092317.24
Fanconi anemia	Pathogenic (1)	criteria provided, single submitter	Aug 29, 2023	RCV000813603.6
FANCA-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 12, 2024	RCV004742563.1

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.
Likely pathogenic (Jul 05, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000792601.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 12697994
Pathogenic (Feb 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370198.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010162.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely pathogenic (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196624.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (Apr 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024571.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000953969.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10094191‚ 12697994‚ 19367192 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 552738). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 10094191, 12697994). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln286*) in the FANCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). (less)
Pathogenic (Dec 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248755.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	Fanconi anemia complementation group A Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001425911.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Publications: PubMed (1) PubMed: 10094191 Comment: Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Pathogenic (Mar 12, 2024)	no assertion criteria provided Method: clinical testing	FANCA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005343157.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The FANCA c.856C>T variant is predicted to result in premature protein termination (p.Gln286). This variant was reported in an individual with Fanconi anemia (Wijker et … (more) The FANCA c.856C>T variant is predicted to result in premature protein termination (p.Gln286). This variant was reported in an individual with Fanconi anemia (Wijker et al 1999. PubMed ID: 10094191). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 552738). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 10094191, 12697994). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln286*) in the FANCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192).

Comment:

The FANCA c.856C>T variant is predicted to result in premature protein termination (p.Gln286*). This variant was reported in an individual with Fanconi anemia (Wijker et al 1999. PubMed ID: 10094191). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.	Gross M	Cytogenetic and genome research	2002	PMID: 12697994
Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.	Wijker M	European journal of human genetics : EJHG	1999	PMID: 10094191

Text-mined citations for rs1291524243 ...

These 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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.856C>T (p.Gln286Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1291524243 ...