NM_000135.2(FANCA):c.1304G>A (p.Arg435His) AND Fanconi anemia

Clinical significance:Likely pathogenic (Last evaluated: Jul 11, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000464366.1

Allele description

NM_000135.2(FANCA):c.1304G>A (p.Arg435His)

Gene:
FANCA:Fanconi anemia complementation group A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_000135.2(FANCA):c.1304G>A (p.Arg435His)
HGVS:
  • NC_000016.10:g.89791458C>T
  • NG_011706.1:g.30200G>A
  • NM_000135.2:c.1304G>A
  • NP_000126.2:p.Arg435His
  • LRG_495t1:c.1304G>A
  • LRG_495:g.30200G>A
  • LRG_495p1:p.Arg435His
  • NC_000016.9:g.89857866C>T
Protein change:
R435H
Links:
dbSNP: rs1060501879
NCBI 1000 Genomes Browser:
rs1060501879
Molecular consequence:
  • NM_000135.2:c.1304G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Fanconi anemia (FA)
Synonyms:
Fanconi's anemia
Identifiers:
MedGen: C0015625; OMIM: PS227650

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000547756Invitae,criteria provided, single submitter
Likely pathogenic
(Jul 11, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae,, SCV000547756.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with histidine at codon 435 of the FANCA protein (p.Arg435His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to occur with a pathogenic variant in FANCA in an individual with Fanconi anemia (PMID: 19367192). While it is unknown if these two variants were on the same or opposite chromosomes, this observation suggests that the c.1304G>A substitution may contribute to the cause of disease. In addition, this variant has been observed in trans with a pathogenic variant in FANCA in an affected individual (Invitae database), further supporting this variant's involvement in disease. A different missense substitution at this codon (p.Arg435Cys) has been determined to be pathogenic (PMID: 12444097, 15523645, 11739169, 10090479). This suggests that the arginine residue is critical for FANCA protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is absent from the population and has been observed in affected individuals. While its effect on protein function is not known, a different variant affecting the same codon disrupts protein function and is known to cause disease. For these reasons, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 4, 2018