NM_000135.4(FANCA):c.4199G>A (p.Arg1400His) AND Fanconi anemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000459562.10

Allele description [Variation Report for NM_000135.4(FANCA):c.4199G>A (p.Arg1400His)]

NM_000135.4(FANCA):c.4199G>A (p.Arg1400His)

Genes:

FANCA:FA complementation group A [Gene - OMIM - HGNC]
ZNF276:zinc finger protein 276 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000135.4(FANCA):c.4199G>A (p.Arg1400His)

HGVS:

NC_000016.10:g.89738943C>T
NG_011706.1:g.82715G>A
NM_000135.4:c.4199G>AMANE SELECT
NM_001113525.2:c.*697C>TMANE SELECT
NM_001286167.3:c.4203G>A
NM_152287.4:c.*697C>T
NP_000126.2:p.Arg1400His
NP_000126.2:p.Arg1400His
NP_001273096.1:p.Ser1401=
LRG_495t1:c.4199G>A
LRG_495:g.82715G>A
LRG_495p1:p.Arg1400His
NC_000016.9:g.89805351C>T
NM_000135.2:c.4199G>A
NR_110122.2:n.2697C>T
NR_110126.2:n.2580C>T
NR_110128.2:n.2520C>T
NR_110129.2:n.2614C>T

Protein change:

R1400H

Links:

dbSNP: rs149851163

NCBI 1000 Genomes Browser:

rs149851163

Molecular consequence:

NM_001113525.2:c.*697C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*697C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000135.4:c.4199G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110122.2:n.2697C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2580C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2520C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2614C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001286167.3:c.4203G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Condition(s)

Name:: Fanconi anemia (FA)
Synonyms:: Fanconi pancytopenia; Fanconi's anemia
Identifiers:: MONDO: MONDO:0019391; MeSH: D005199; MedGen: C0015625; Orphanet: 84; OMIM: PS227650

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000547747	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17924555, 15643609, 21273304, 24584348, 28102861, 28717661, 29098742, 28492532
SCV002103354	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17924555, 26580448, 28717661, 29098742, 33172906, 33686268 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000547747

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002103354

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 13, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.

Levran O, Diotti R, Pujara K, Batish SD, Hanenberg H, Auerbach AD.

Hum Mutat. 2005 Feb;25(2):142-9.

PubMed [citation]

PMID:: 15643609

Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.

Castella M, Pujol R, Callén E, Trujillo JP, Casado JA, Gille H, Lach FP, Auerbach AD, Schindler D, Benítez J, Porto B, Ferro T, Muñoz A, Sevilla J, Madero L, Cela E, Beléndez C, de Heredia CD, Olivé T, de Toledo JS, Badell I, Torrent M, et al.

Blood. 2011 Apr 7;117(14):3759-69. doi: 10.1182/blood-2010-08-299917. Epub 2011 Jan 27.

PubMed [citation]

PMID:: 21273304
PMCID:: PMC3083295

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000547747.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1400 of the FANCA protein (p.Arg1400His). This variant is present in population databases (rs149851163, gnomAD 0.006%). This missense change has been observed in individuals with Fanconi anemia (PMID: 17924555, 29098742). ClinVar contains an entry for this variant (Variation ID: 408175). 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%. This variant disrupts the p.Arg1400 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15643609, 21273304, 24584348, 28102861, 28717661, 29098742). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002103354.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: FANCA c.4199G>A (p.Arg1400His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251486 control chromosomes (gnomAD). c.4199G>A has been reported in the literature in multiple compound heterozygous individuals diagnosed with Fanconi Anemia, where the diagnosis had been established by chromosomal breakage test (Ameziane_2008, Kimble_2018, Lach_2020), however 2 of these cases (brothers) had an atypical, delayed phenotype (i.e. presenting with esophageal malignancies at the age of 51y, with the lack of hematologic failure), and were subsequently diagnosed to have FA by chromosomal breakage and molecular testing (Lach_2020). Publications have also reported experimental evidence evaluating an impact on protein function. In an early study, expression of the R1400H variant in lymphoblastoid cell lines lacking functional FANCA protein demonstrated similar activity to the wild type, however due to overexpression of the construct, a potential hypomorphic effect couldn't be ruled out (Ameziane_2008). A later, more detailed study demonstrated a reduced protein level, and increased cytoplasmic localization, together with a mild decrease in Fancd2 ubiquitination and foci formation, and increased sensitivity to DNA cross-linking agents, providing evidence for a hypomorphic effect (Lach_2020). The following publications have been ascertained in the context of this evaluation (PMID: 17924555, 29098742, 33172906, 28717661, 33686268, 26580448). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three submitters classified the variant as pathogenic/likely pathogenic and three classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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