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

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 24, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000779200.12

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 complementation group A
Synonyms:: Fanconi anemia, group A
Identifiers:: MONDO: MONDO:0009215; MedGen: C3469521; Orphanet: 84; OMIM: 227650

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915736	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Feb 6, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17924555, 24584348 Citation Link,
SCV001426666	International Fanconi Anemia Registry, The Rockefeller University	no assertion criteria provided	Likely pathogenic (Aug 5, 2020)	not applicable	in vitro
SCV001458740	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002060088	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 11, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33172906, 17924555, 29098742 Citation Link,
SCV004196033	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 24, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

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, Bottega R, Cappelli E, Cavani S, Criscuolo M, Nicchia E, Corsolini F, Greco C, Borriello A, Svahn J, Pillon M, Mecucci C, Casazza G, Verzegnassi F, Cugno C, Locasciulli A, Farruggia P, Longoni D, Ramenghi U, Barberi W, Tucci F, Perrotta S, et al.

Haematologica. 2014 Jun;99(6):1022-31. doi: 10.3324/haematol.2014.104224. Epub 2014 Feb 28. Erratum in: Haematologica. 2014 Sep;99(9):1532.

PubMed [citation]

PMID:: 24584348
PMCID:: PMC4040906

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant.

Lach FP, Singh S, Rickman KA, Ruiz PD, Noonan RJ, Hymes KB, DeLacure MD, Kennedy JA, Chandrasekharappa SC, Smogorzewska A.

Cold Spring Harb Mol Case Stud. 2020 Dec 17;6(6). doi:pii: a005595. 10.1101/mcs.a005595. Print 2020 Dec.

PubMed [citation]

PMID:: 33172906
PMCID:: PMC7784490

See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915736.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The FANCA c.4199G>A (p.Arg1400His) variant has been reported in two studies and is found in two individuals with Fanconi anemia, including one in a compound heterozygous state with a missense variant and one in a heterozygous state in whom a second variant was not identified (Ameziane et al. 2008; De Rocco et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Arg1400His variant in lymphoblastoid cell lines lacking functional FANCA protein demonstrated an activity similar to wild type protein, however, compensation due to overexpression of the p.Arg1400His protein could not be ruled out (Ameziane et al. 2008). The evidence for this variant is limited. The variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 International Fanconi Anemia Registry, The Rockefeller University, SCV001426666.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	not provided

Description

The c.4199G>A/p.R1400H variant was previously reported in an individual with Fanconi anemia, but determining pathogenicity was difficult because it was reported that overexpression of the mutant allele resulted in complementation comparable to that obtained with the wild type cDNA (Ameziane et al. 2008). This suggests that overexpression of the mutant protein is able to compensate for protein instability and/or defects in FANCA protein function. We have identified c.4199G>A/p.R1400H variant in another FA family (two affected brothers) in trans with a c.3788_3790delTCT, a known pathogenic variant. Our functional data support the variant as a most likely pathogenic allele. We observe increased mislocalization of mutant protein to the cytoplasm, decreased FANCD2 ubiquitination and foci formation, and cellular sensitivity to crosslinking agents. We have examined the variant by CRISPR/Cas9 mediated genome editing in otherwise wild type fibroblast cell lines and we showed that the R1400H variant in homozygous form had an incomplete loss of function (behaved as a hypomorph), and the cellular phenotype characteristic of Fanconi anemia was further exacerbated when it was present in trans to a loss-of-function allele, indicating a dose effect of a mutant protein.

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

From Natera, Inc., SCV001458740.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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 Myriad Genetics, Inc., SCV002060088.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

NM_000135.2(FANCA):c.4199G>A(R1400H) is a missense variant classified as a variant of uncertain significance in the context of Fanconi anemia complementation group A. R1400H has been observed in cases with relevant disease (PMID: 17924555, 29098742, 33172906). Functional assessments of this variant are available in the literature (PMID: 17924555, 33172906). R1400H has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_000135.2(FANCA):c.4199G>A(R1400H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

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

From Baylor Genetics, SCV004196033.2

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

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

Last Updated: Sep 1, 2024

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