VCV000555969.16 - ClinVar

NM_000135.4(FANCA):c.2738A>C (p.His913Pro)

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.

(7)

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.2738A>C (p.His913Pro)

Variation ID: 555969 Accession: VCV000555969.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89764930 (GRCh38) [ NCBI UCSC ] 16: 89831338 (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	Jun 17, 2024	Mar 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.2738A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000126.2:p.His913Pro	missense
NM_001286167.3:c.2738A>C	NP_001273096.1:p.His913Pro	missense
NC_000016.10:g.89764930T>G
NC_000016.9:g.89831338T>G
NG_011706.1:g.56728A>C
LRG_495:g.56728A>C
LRG_495t1:c.2738A>C

... more HGVS ... less HGVS

Protein change

H913P

Other names

Canonical SPDI

NC_000016.10:89764929:T:G

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: rs1302083447 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	4166	5324

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	Mar 3, 2024	RCV000671893.7
Fanconi anemia	Pathogenic (1)	criteria provided, single submitter	Jan 24, 2024	RCV000796523.8
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2019	RCV001816676.4

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 (Jan 04, 2018)	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: SCV000796926.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 24584348‚ 15643609
Likely pathogenic (Jul 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000891230.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 29269525‚ 24584348‚ 29093742 Number of individuals with the variant: 1
Pathogenic (Jul 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064667.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.2621G>C in exon 28, which results in an amino acid change, p.Arg874Thr. The p.Arg874Thr … (more) DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.2621G>C in exon 28, which results in an amino acid change, p.Arg874Thr. The p.Arg874Thr 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.Arg874Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL, in silico splice prediction programs). This sequence change is absent from large population databases such as ExAC and gnomAD. The p.Arg874Thr amino acid change occurs in a region of the FANCA gene where other missense sequence changes have been described in patients with FANCA-related disorders (PMIDs: 15643609, 24116929). This sequence change was identified with another likely pathogenic FANCA variant in a patient. (less)
Likely pathogenic (Dec 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002801433.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 24, 2024)	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: SCV000936041.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 29098742‚ 29269525 Comment: This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 913 of the FANCA protein (p.His913Pro). … (more) This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 913 of the FANCA protein (p.His913Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Fanconi anemia (PMID: 29098742, 29269525). ClinVar contains an entry for this variant (Variation ID: 555969). 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 not expected to disrupt FANCA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 29269525). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196595.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
not provided (-)	no classification provided Method: literature only	Fanconi anemia complementation group A Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001737413.2 First in ClinVar: Jun 19, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301575‚ 29269525 BookShelf: NBK1401 BookShelf: NBK1401 Comment: Associated with slower hematologic disease progression

Comment:

DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.2621G>C in exon 28, which results in an amino acid change, p.Arg874Thr. The p.Arg874Thr 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.Arg874Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL, in silico splice prediction programs). This sequence change is absent from large population databases such as ExAC and gnomAD. The p.Arg874Thr amino acid change occurs in a region of the FANCA gene where other missense sequence changes have been described in patients with FANCA-related disorders (PMIDs: 15643609, 24116929). This sequence change was identified with another likely pathogenic FANCA variant in a patient.

Comment:

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 913 of the FANCA protein (p.His913Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Fanconi anemia (PMID: 29098742, 29269525). ClinVar contains an entry for this variant (Variation ID: 555969). 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 not expected to disrupt FANCA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 29269525). For these reasons, this variant has been classified 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
Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia.	Bottega R	Haematologica	2018	PMID: 29269525
A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families.	Kimble DC	Human mutation	2018	PMID: 29098742
Integrative field scale phenotyping for investigating metabolic components of water stress within a vineyard.	Gago J	Plant methods	2017	PMID: 29093742
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
Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.	Levran O	Human mutation	2005	PMID: 15643609

Text-mined citations for rs1302083447 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.2738A>C (p.His913Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1302083447 ...