NM_000135.4(FANCA):c.4198C>T (p.Arg1400Cys) AND Fanconi anemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 9, 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:: RCV000801328.9

Allele description [Variation Report for NM_000135.4(FANCA):c.4198C>T (p.Arg1400Cys)]

NM_000135.4(FANCA):c.4198C>T (p.Arg1400Cys)

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.4198C>T (p.Arg1400Cys)

HGVS:

NC_000016.10:g.89738944G>A
NG_011706.1:g.82714C>T
NM_000135.4:c.4198C>TMANE SELECT
NM_001113525.2:c.*698G>AMANE SELECT
NM_001286167.3:c.4202C>T
NM_152287.4:c.*698G>A
NP_000126.2:p.Arg1400Cys
NP_000126.2:p.Arg1400Cys
NP_001273096.1:p.Ser1401Leu
LRG_495t1:c.4198C>T
LRG_495:g.82714C>T
LRG_495p1:p.Arg1400Cys
NC_000016.9:g.89805352G>A
NM_000135.2:c.4198C>T
NR_110122.2:n.2698G>A
NR_110126.2:n.2581G>A
NR_110128.2:n.2521G>A
NR_110129.2:n.2615G>A

Protein change:

R1400C

Links:

dbSNP: rs745882980

NCBI 1000 Genomes Browser:

rs745882980

Molecular consequence:

NM_001113525.2:c.*698G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*698G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000135.4:c.4198C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286167.3:c.4202C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_110122.2:n.2698G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2581G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2521G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2615G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000941102	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17924555, 30792206, 15643609, 21273304, 24584348, 28102861, 28717661, 29098742, 28492532
SCV001983401	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 28, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24584348, 28717661, 30792206, 29098742, 21273304, 15643609, 28102861 Citation Link,
SCV002092470	Natera, Inc.	no assertion criteria provided	Pathogenic (May 27, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000941102

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001983401

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 28, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV002092470

Natera, Inc.

no assertion criteria provided

Pathogenic
(May 27, 2021)

germline

clinical testing

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

Genetic subtyping of Fanconi anemia by comprehensive mutation screening.

Ameziane N, Errami A, Léveillé F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H.

Hum Mutat. 2008 Jan;29(1):159-66.

PubMed [citation]

PMID:: 17924555

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000941102.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant disrupts the p.Arg1400 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been observed in individuals with FANCA-related conditions (PMID: 17924555, 29098742, 30792206), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 554887). This missense change has been observed in individuals with Fanconi anemia (PMID: 15643609, 21273304, 24584348, 28102861, 28717661, 29098742). This variant is present in population databases (rs745882980, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1400 of the FANCA protein (p.Arg1400Cys). 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, SCV001983401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: FANCA c.4198C>T (p.Arg1400Cys) 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 1.2e-05 in 251486 control chromosomes. c.4198C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia (example, Levran_2005, Castella_2011, De Rocco_2014, Muramatsu_2017, Pilonetto_2017, Kimble_2018, Mori_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV002092470.1

#	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

Last Updated: Sep 1, 2024

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